5-Lipoxygenase: The Therapeutically Unexplored Target for Bone Health
,
Abstract
Bone fracture is a common orthopedic condition that represents a significant health concern. Bone fracture repair process is a complex process that involves the harmonic and synchronized activity of bone cells. 5-lipoxygenase (5-LOX) is an enzyme responsible for the conversion of arachidonic acid to form leukotrienes. While leukotrienes have an empirical inflammatory role, various evidence suggests that these 5-LOX mediators, by switching the inflammatory environment and altering the activity of bone cells, have a detrimental effect on the bone fracture healing process. Additionally, various evidence suggests that 5-LOX inhibition shows improvement in the overall bone healing process and improves overall bone health. Despite this evidence, the clinical use of 5-LOX inhibitors in bone fracture healing is largely unexplored. The current review aimed to summarize the available evidence and pave the way for future large scale pre-clinical and clinical studies to evaluate the effectiveness of selective 5-LOX inhibitors in bone fracture healing.
1. Datta HK, Ng WF, Walker JA, Tuck SP, Varanasi SS. The cell biology of bone metabolism. J Clin Pathol. 2008;61(5):577–87.
2. Gerard J. Tortora, Bryan Derrickson. Principles of Anatomy and Physiology. 14th ed. John Wiley & Sons; 2014. p. 169–191.
3. Florencio-Silva R, Sasso GR da S, Sasso-Cerri E, Simões MJ, Cerri PS. Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells. Biomed Res Int. 2015;2015:1–17.
4. Castillo AB, Leucht P. Bone Homeostasis and Repair: Forced Into Shape. Curr Rheumatol Rep. 2015;17(9):58.
5. Mödinger Y, Löffler B, Huber-Lang M, Ignatius A. Complement involvement in bone homeostasis and bone disorders. Semin Immunol. 2018;37:53–65.
6. Ghiasi MS, Chen J, Vaziri A, Rodriguez EK, Nazarian A. Bone fracture healing in mechanobiological modeling: A review of principles and methods. Bone Rep. 2017;6:87–100.
7. Syed MA, Azim SR, Baig M. Frequency of orthopedic problems among patients attending an orthopedic outpatient department: a retrospective analysis of 23 495 cases. Ann Saudi Med. 2019;39(3):172–7.
8. Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet. 2011;377(9773):1276– 87.
9. Tarantino U, Piccirilli E, Fantini M, Baldi J, Gasbarra E, Bei R. Sarcopenia and fragility fractures: molecular and clinical evidence of the bone-muscle interaction. J Bone Joint Surg. 2015;97(5):429–37.
10. Hars M, Biver E, Chevalley T, et al. Low lean mass predicts incident fractures independently from frax: a prospective cohort study of recent retirees. J Bone Miner Res. 2016;31(11):2048–56.
11. Bigham-Sadegh A, Oryan A. Basic concepts regarding fracture healing and the current options and future directions in managing bone fractures. Int Wound J. 2015;12(3):238–47.
12. Wu AM, Bisignano C, James SL, et al. Global, regional, and national burden of bone fractures in 204 countries and territories, 1990–2019: a systematic analysis from the Global Burden of Disease Study 2019. Lancet Healthy Longev. 2021;2(9):e580–92.
13. Ross PD. Clinical consequences of vertebral fractures. Am J Med. 1997;103(2):S30–43.
14. Baertl S, Alt V, Rupp M. Surgical enhancement of fracture healing – operative vs. nonoperative treatment. Injury. 2021;52:S12–7.
15. Perracini MR, Kristensen MT, Cunningham C, Sherrington C. Physiotherapy following fragility fractures. Injury. 2018;49(8):1413–7.
16. Bruder AM, Taylor NF, Dodd KJ, Shields N. Physiotherapy intervention practice patterns used in rehabilitation after distal radial fracture. Physiotherapy. 2013;99(3):233–40.
17. Wakefield AE, McQueen MM. The role of physiotherapy and clinical predictors of outcome after fracture of the distal radius. J Bone Joint Surg. 2000;82(7):972–6.
18. Fischer V, Haffner-Luntzer M, Amling M, Ignatius A. Calcium and vitamin D in bone fracture healing and post-traumatic bone turnover. Eur Cell Mater. 2018;35:365–85.
19. Bodenner D, Redman C, Riggs A. Teriparatide in the management of osteoporosis. Clin Interv Aging. 2007;2(4):499-507.
20. Kates SL, Ackert-Bicknell CL. How do bisphosphonates affect fracture healing? Injury. 2016;47:S65–8. 21. Agarwala S, Vijayvargiya M. Repurposing denosumab for recalcitrant bone healing. BMJ Case Rep. 2021;14(2):e238460.
22. Roy A, Thulasiraman S, Panneerselvam E, et al. Evaluation of the efficacy of salmon calcitonin nasal spray on bone healing following open reduction and internal fixation of mandibular fractures: A randomized controlled trial. J Craniomaxillofac Surg. 2021;49(12):1151–7.
23. Beil FT, Barvencik F, Gebauer M, et al. Effects of Estrogen on Fracture Healing in Mice. J Trauma. 2010;69(5):1259–65.
24. Tahami M, Haddad B, Abtahian A, Hashemi A, Aminian A, Konan S. Potential role of local estrogen in enhancement of fracture healing: preclinical study in rabbits. Arch Bone Jt Surg. 2016;4(4):323–9.
25. Brahmkshatriya H, Shah K, Ananthkumar G, Brahmkshatriya M. Clinical evaluation of Cissus quadrangularis as osteogenic agent in maxillofacial fracture: A pilot study. Ayu. 2015;36(2):169.
26. Maruyama M, Rhee C, Utsunomiya T, et al. Modulation of the inflammatory response and bone healing. Front Endocrinol. 2020;11.
27. Bigham‐Sadegh A, Oryan A. Basic concepts regarding fracture healing and the current options and future directions in managing bone fractures. Int Wound J. 2015;12(3):238–47.
28. Roberts TT, Rosenbaum AJ. Bone grafts, bone substitutes and orthobiologics. Organogenesis. 2012;8(4):114–24.
29. Schell H, Duda GN, Peters A, Tsitsilonis S, Johnson KA, Schmidt-Bleek K. The haematoma and its role in bone healing. J Exp Orthop. 2017;4(1):5.
30. Shiu HT, Leung PC, Ko CH. The roles of cellular and molecular components of a hematoma at early stage of bone healing. J Tissue Eng Regen Med. 2018;12(4):e1911–25.
31. Giannoudis P V., Hak D, Sanders D, Donohoe E, Tosounidis T, Bahney C. Inflammation, bone healing, and anti-inflammatory drugs. J Orthop Trauma. 2015;29(Suppl 12):S6–9.
32. Lin HN, O’Connor JP. Immunohistochemical localization of key arachidonic acid metabolism enzymes during fracture healing in mice. PLoS One. 2014;9(2):e88423.
33. Xie C, Ming X, Wang Q, et al. COX-2 from the injury milieu is critical for the initiation of periosteal progenitor cell mediated bone healing. Bone. 2008;43(6):1075–83.
34. Ren W, Dziak R. Effects of leukotrienes on osteoblastic cell proliferation. Calcif Tissue Int. 1991;49(3):197–201.
35. Schindeler A, McDonald MM, Bokko P, Little DG. Bone remodeling during fracture repair: The cellular picture. Semin Cell Dev Biol. 2008;19(5):459–66.
36. Akino K, Mineda T, Mori N, Hirano A, Imaizumi T, Akita S. Attenuation of cysteinyl leukotrienes induces human mesenchymal stem cell differentiation. Wound Repair Regen. 2006;14(3):343–9.
37. Ford-Hutchinson AW, Gresser M, Young RN. 5-Lipoxygenase. Annu Rev Biochem. 1994;63(1):383–417.
38. Werz O. 5-Lipoxygenase: cellular biology and molecular pharmacology. Curr Drug Targets Inflamm Allergy. 2002;1(1):23–44.
39. Matsumoto T, Funk CD, Rådmark O, Höög JO, Jörnvall H, Samuelsson B. Molecular cloning and amino acid sequence of human 5-lipoxygenase. Proc Natl Acad Sci U S A. 1988;85(1):26–30.
40. Sinha S, Doble M, Manju SL. 5-Lipoxygenase as a drug target: A review on trends in inhibitors structural design, SAR and mechanism based approach. Bioorg Med Chem. 2019;27(17):3745–59.
41. Rask-Madsen J, Bukhave K, Laursen LS, Lauritsen K. 5-Lipoxygenase inhibitors for the treatment of inflammatory bowel disease. Agents Actions. 1992;Spec No:C37-46.
42. Ayola-Serrano NC, Roy N, Fathah Z, et al. The role of 5-lipoxygenase in the pathophysiology of COVID-19 and its therapeutic implications. Inflamm Res. 2021;70(8):877–89.
43. Suva MA, Kheni DB, Sureja VP. Aflapin: A novel and selective 5-lipoxygenase inhibitor for arthritis management. Indian Journal of Pain. 2018;32(1):16.
44. Lee JM, Park H, Noh ALSM, et al. 5-Lipoxygenase Mediates RANKL-Induced osteoclast formation via the cysteinyl leukotriene receptor 1. J Immunol. 2012;189(11):5284–92.
45. Gallwitz WE, Mundy GR, Lee CH, et al. 5-Lipoxygenase metabolites of arachidonic acid stimulate isolated osteoclasts to resorb calcified matrices. J Biol Chem. 1993;268(14):10087–94.
46. Park JH, Lee NK, Lee SY. Current understanding of RANK signaling in osteoclast differentiation and maturation. Mol Cells. 2017;40(10):706–13.
47. Paula-Silva FWG, Petean IBF, da Silva LAB, Faccioli LH. Dual role of 5-lipoxygenase in osteoclastogenesis in bacterial-induced apical periodontitis. J Endod. 2016;42(3):447–54.
48. Lopes DEM, Jabr CL, Dejani NN, et al. Inhibition of 5-Lipoxygenase (5-Lo) attenuates inflammation and bone resorption in lipopolysaccharide (lps)-induced periodontal Disease. J Periodontol. 2017;1–18. 49. Traianedes K, Dallas MR, Garrett IR, Mundy GR, Bonewald LF. 5-Lipoxygenase metabolites inhibit bone formation in Vitro. Endocrinology. 1998;139(7):3178–84.
50. Manigrasso MB, O’Connor JP. Accelerated fracture healing in mice lacking the 5-lipoxygenase gene. Acta Orthop. 2010;81(6):748–55.
51. Wixted JJ, Fanning PJ, Gaur T, et al. Enhanced fracture repair by leukotriene antagonism is characterized by increased chondrocyte proliferation and early bone formation: A novel role of the cysteinyl LT‐1 receptor. J Cell Physiol. 2009;221(1):31–9.
52. Cottrell JA, OʼConnor JP. Pharmacological inhibition of 5-lipoxygenase accelerates and enhances fracture healing. J Bone Joint Surg. 2009;91(11):2653–65.
53. Cottrell JA, Keshav V, Mitchell A, O’Connor JP. Local inhibition of 5-lipoxygenase enhances bone formation in a rat model. Bone Joint Res. 2013;2(2):41–50.
54. Biguetti CC, Couto MCR, Silva ACR, et al. New surgical model for bone–muscle injury reveals age and gender-related healing patterns in the 5 lipoxygenase (5lo) knockout mouse. Front Endocrinol. 2020;11.
55. Saul D, Hohl FE, Franz MK, et al. Inhibition of lipoxygenases showed no benefit for the
musculoskeletal system in estrogen deficient rats. Front Endocrinol. 2021;12.
56. Saul D, Weber M, Zimmermann MH, et al. Effect of the lipoxygenase inhibitor baicalein on bone tissue and bone healing in ovariectomized rats. Nutr Metab. 2019;16(1):4.
57. Bruderer M, Richards R, Alini M, Stoddart M. Role and regulation of runx2 in osteogenesis. Eur Cell Mater. 2014;28:269–86.
58. Komori T. Regulation of proliferation, differentiation and functions of osteoblasts by runx2. Int J Mol Sci. 2019;20(7):1694.
59. Chiu WK, Vien BS, Russ M, Fitzgerald M. Healing assessment of fractured femur treated with an intramedullary nail. Struct Health Monit. 2021;20(3):782–90.
60. Bong MR, Kummer FJ, Koval KJ, Egol KA. Intramedullary nailing of the lower extremity: biomechanics and biology. J Am Acad Orthop Surg. 2007;15(2):97–106.
61. Khazai N, Judd SE,1. Datta HK, Ng WF, Walker JA, Tuck SP, Varanasi SS. The cell biology of bone metabolism. J Clin Pathol. 2008;61(5):577–87.
2. Gerard J. Tortora, Bryan Derrickson. Principles of Anatomy and Physiology. 14th ed. John Wiley & Sons; 2014. p. 169–191.
3. Florencio-Silva R, Sasso GR da S, Sasso-Cerri E, Simões MJ, Cerri PS. Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells. Biomed Res Int. 2015;2015:1–17.
4. Castillo AB, Leucht P. Bone Homeostasis and Repair: Forced Into Shape. Curr Rheumatol Rep. 2015;17(9):58.
5. Mödinger Y, Löffler B, Huber-Lang M, Ignatius A. Complement involvement in bone homeostasis and bone disorders. Semin Immunol. 2018;37:53–65.
6. Ghiasi MS, Chen J, Vaziri A, Rodriguez EK, Nazarian A. Bone fracture healing in mechanobiological modeling: A review of principles and methods. Bone Rep. 2017;6:87–100.
7. Syed MA, Azim SR, Baig M. Frequency of orthopedic problems among patients attending an orthopedic outpatient department: a retrospective analysis of 23 495 cases. Ann Saudi Med. 2019;39(3):172–7.
8. Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet. 2011;377(9773):1276– 87.
9. Tarantino U, Piccirilli E, Fantini M, Baldi J, Gasbarra E, Bei R. Sarcopenia and fragility fractures: molecular and clinical evidence of the bone-muscle interaction. J Bone Joint Surg. 2015;97(5):429–37.
10. Hars M, Biver E, Chevalley T, et al. Low lean mass predicts incident fractures independently from frax: a prospective cohort study of recent retirees. J Bone Miner Res. 2016;31(11):2048–56.
11. Bigham-Sadegh A, Oryan A. Basic concepts regarding fracture healing and the current options and future directions in managing bone fractures. Int Wound J. 2015;12(3):238–47.
12. Wu AM, Bisignano C, James SL, et al. Global, regional, and national burden of bone fractures in 204 countries and territories, 1990–2019: a systematic analysis from the Global Burden of Disease Study 2019. Lancet Healthy Longev. 2021;2(9):e580–92.
13. Ross PD. Clinical consequences of vertebral fractures. Am J Med. 1997;103(2):S30–43.
14. Baertl S, Alt V, Rupp M. Surgical enhancement of fracture healing – operative vs. nonoperative treatment. Injury. 2021;52:S12–7.
15. Perracini MR, Kristensen MT, Cunningham C, Sherrington C. Physiotherapy following fragility fractures. Injury. 2018;49(8):1413–7.
16. Bruder AM, Taylor NF, Dodd KJ, Shields N. Physiotherapy intervention practice patterns used in rehabilitation after distal radial fracture. Physiotherapy. 2013;99(3):233–40.
17. Wakefield AE, McQueen MM. The role of physiotherapy and clinical predictors of outcome after fracture of the distal radius. J Bone Joint Surg. 2000;82(7):972–6.
18. Fischer V, Haffner-Luntzer M, Amling M, Ignatius A. Calcium and vitamin D in bone fracture healing and post-traumatic bone turnover. Eur Cell Mater. 2018;35:365–85.
19. Bodenner D, Redman C, Riggs A. Teriparatide in the management of osteoporosis. Clin Interv Aging. 2007;2(4):499-507.
20. Kates SL, Ackert-Bicknell CL. How do bisphosphonates affect fracture healing? Injury. 2016;47:S65–8. 21. Agarwala S, Vijayvargiya M. Repurposing denosumab for recalcitrant bone healing. BMJ Case Rep. 2021;14(2):e238460.
22. Roy A, Thulasiraman S, Panneerselvam E, et al. Evaluation of the efficacy of salmon calcitonin nasal spray on bone healing following open reduction and internal fixation of mandibular fractures: A randomized controlled trial. J Craniomaxillofac Surg. 2021;49(12):1151–7.
23. Beil FT, Barvencik F, Gebauer M, et al. Effects of Estrogen on Fracture Healing in Mice. J Trauma. 2010;69(5):1259–65.
24. Tahami M, Haddad B, Abtahian A, Hashemi A, Aminian A, Konan S. Potential role of local estrogen in enhancement of fracture healing: preclinical study in rabbits. Arch Bone Jt Surg. 2016;4(4):323–9.
25. Brahmkshatriya H, Shah K, Ananthkumar G, Brahmkshatriya M. Clinical evaluation of Cissus quadrangularis as osteogenic agent in maxillofacial fracture: A pilot study. Ayu. 2015;36(2):169.
26. Maruyama M, Rhee C, Utsunomiya T, et al. Modulation of the inflammatory response and bone healing. Front Endocrinol. 2020;11.
27. Bigham‐Sadegh A, Oryan A. Basic concepts regarding fracture healing and the current options and future directions in managing bone fractures. Int Wound J. 2015;12(3):238–47.
28. Roberts TT, Rosenbaum AJ. Bone grafts, bone substitutes and orthobiologics. Organogenesis. 2012;8(4):114–24.
29. Schell H, Duda GN, Peters A, Tsitsilonis S, Johnson KA, Schmidt-Bleek K. The haematoma and its role in bone healing. J Exp Orthop. 2017;4(1):5.
30. Shiu HT, Leung PC, Ko CH. The roles of cellular and molecular components of a hematoma at early stage of bone healing. J Tissue Eng Regen Med. 2018;12(4):e1911–25.
31. Giannoudis P V., Hak D, Sanders D, Donohoe E, Tosounidis T, Bahney C. Inflammation, bone healing, and anti-inflammatory drugs. J Orthop Trauma. 2015;29(Suppl 12):S6–9.
32. Lin HN, O’Connor JP. Immunohistochemical localization of key arachidonic acid metabolism enzymes during fracture healing in mice. PLoS One. 2014;9(2):e88423.
33. Xie C, Ming X, Wang Q, et al. COX-2 from the injury milieu is critical for the initiation of periosteal progenitor cell mediated bone healing. Bone. 2008;43(6):1075–83.
34. Ren W, Dziak R. Effects of leukotrienes on osteoblastic cell proliferation. Calcif Tissue Int. 1991;49(3):197–201.
35. Schindeler A, McDonald MM, Bokko P, Little DG. Bone remodeling during fracture repair: The cellular picture. Semin Cell Dev Biol. 2008;19(5):459–66.
36. Akino K, Mineda T, Mori N, Hirano A, Imaizumi T, Akita S. Attenuation of cysteinyl leukotrienes induces human mesenchymal stem cell differentiation. Wound Repair Regen. 2006;14(3):343–9.
37. Ford-Hutchinson AW, Gresser M, Young RN. 5-Lipoxygenase. Annu Rev Biochem. 1994;63(1):383–417.
38. Werz O. 5-Lipoxygenase: cellular biology and molecular pharmacology. Curr Drug Targets Inflamm Allergy. 2002;1(1):23–44.
39. Matsumoto T, Funk CD, Rådmark O, Höög JO, Jörnvall H, Samuelsson B. Molecular cloning and amino acid sequence of human 5-lipoxygenase. Proc Natl Acad Sci U S A. 1988;85(1):26–30.
40. Sinha S, Doble M, Manju SL. 5-Lipoxygenase as a drug target: A review on trends in inhibitors structural design, SAR and mechanism based approach. Bioorg Med Chem. 2019;27(17):3745–59.
41. Rask-Madsen J, Bukhave K, Laursen LS, Lauritsen K. 5-Lipoxygenase inhibitors for the treatment of inflammatory bowel disease. Agents Actions. 1992;Spec No:C37-46.
42. Ayola-Serrano NC, Roy N, Fathah Z, et al. The role of 5-lipoxygenase in the pathophysiology of COVID-19 and its therapeutic implications. Inflamm Res. 2021;70(8):877–89.
43. Suva MA, Kheni DB, Sureja VP. Aflapin: A novel and selective 5-lipoxygenase inhibitor for arthritis management. Indian Journal of Pain. 2018;32(1):16.
44. Lee JM, Park H, Noh ALSM, et al. 5-Lipoxygenase Mediates RANKL-Induced osteoclast formation via the cysteinyl leukotriene receptor 1. J Immunol. 2012;189(11):5284–92.
45. Gallwitz WE, Mundy GR, Lee CH, et al. 5-Lipoxygenase metabolites of arachidonic acid stimulate isolated osteoclasts to resorb calcified matrices. J Biol Chem. 1993;268(14):10087–94.
46. Park JH, Lee NK, Lee SY. Current understanding of RANK signaling in osteoclast differentiation and maturation. Mol Cells. 2017;40(10):706–13.
47. Paula-Silva FWG, Petean IBF, da Silva LAB, Faccioli LH. Dual role of 5-lipoxygenase in osteoclastogenesis in bacterial-induced apical periodontitis. J Endod. 2016;42(3):447–54.
48. Lopes DEM, Jabr CL, Dejani NN, et al. Inhibition of 5-Lipoxygenase (5-Lo) attenuates inflammation and bone resorption in lipopolysaccharide (lps)-induced periodontal Disease. J Periodontol. 2017;1–18. 49. Traianedes K, Dallas MR, Garrett IR, Mundy GR, Bonewald LF. 5-Lipoxygenase metabolites inhibit bone formation in Vitro. Endocrinology. 1998;139(7):3178–84.
50. Manigrasso MB, O’Connor JP. Accelerated fracture healing in mice lacking the 5-lipoxygenase gene. Acta Orthop. 2010;81(6):748–55.
51. Wixted JJ, Fanning PJ, Gaur T, et al. Enhanced fracture repair by leukotriene antagonism is characterized by increased chondrocyte proliferation and early bone formation: A novel role of the cysteinyl LT‐1 receptor. J Cell Physiol. 2009;221(1):31–9.
52. Cottrell JA, OʼConnor JP. Pharmacological inhibition of 5-lipoxygenase accelerates and enhances fracture healing. J Bone Joint Surg. 2009;91(11):2653–65.
53. Cottrell JA, Keshav V, Mitchell A, O’Connor JP. Local inhibition of 5-lipoxygenase enhances bone formation in a rat model. Bone Joint Res. 2013;2(2):41–50.
54. Biguetti CC, Couto MCR, Silva ACR, et al. New surgical model for bone–muscle injury reveals age and gender-related healing patterns in the 5 lipoxygenase (5lo) knockout mouse. Front Endocrinol. 2020;11.
55. Saul D, Hohl FE, Franz MK, et al. Inhibition of lipoxygenases showed no benefit for the
musculoskeletal system in estrogen deficient rats. Front Endocrinol. 2021;12.
56. Saul D, Weber M, Zimmermann MH, et al. Effect of the lipoxygenase inhibitor baicalein on bone tissue and bone healing in ovariectomized rats. Nutr Metab. 2019;16(1):4.
57. Bruderer M, Richards R, Alini M, Stoddart M. Role and regulation of runx2 in osteogenesis. Eur Cell Mater. 2014;28:269–86.
58. Komori T. Regulation of proliferation, differentiation and functions of osteoblasts by runx2. Int J Mol Sci. 2019;20(7):1694.
59. Chiu WK, Vien BS, Russ M, Fitzgerald M. Healing assessment of fractured femur treated with an intramedullary nail. Struct Health Monit. 2021;20(3):782–90.
60. Bong MR, Kummer FJ, Koval KJ, Egol KA. Intramedullary nailing of the lower extremity: biomechanics and biology. J Am Acad Orthop Surg. 2007;15(2):97–106.
61. Khazai N, Judd SE, Tangpricha V. Calcium and vitamin D: Skeletal and extraskeletal health. Curr Rheumatol Rep. 2008;10(2):110–7.
62. Muthusami S, Senthilkumar K, Vignesh C, et al. Effects of Cissus quadrangularis on the proliferation, differentiation and matrix mineralization of human osteoblast like SaOS‐2 cells. J Cell Biochem. 2011;112(4):1035–45
1. Datta HK, Ng WF, Walker JA, Tuck SP, Varanasi SS. The cell biology of bone metabolism. J Clin Pathol. 2008;61(5):577–87.
2. Gerard J. Tortora, Bryan Derrickson. Principles of Anatomy and Physiology. 14th ed. John Wiley & Sons; 2014. p. 169–191.
3. Florencio-Silva R, Sasso GR da S, Sasso-Cerri E, Simões MJ, Cerri PS. Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells. Biomed Res Int. 2015;2015:1–17.
4. Castillo AB, Leucht P. Bone Homeostasis and Repair: Forced Into Shape. Curr Rheumatol Rep. 2015;17(9):58.
5. Mödinger Y, Löffler B, Huber-Lang M, Ignatius A. Complement involvement in bone homeostasis and bone disorders. Semin Immunol. 2018;37:53–65.
6. Ghiasi MS, Chen J, Vaziri A, Rodriguez EK, Nazarian A. Bone fracture healing in mechanobiological modeling: A review of principles and methods. Bone Rep. 2017;6:87–100.
7. Syed MA, Azim SR, Baig M. Frequency of orthopedic problems among patients attending an orthopedic outpatient department: a retrospective analysis of 23 495 cases. Ann Saudi Med. 2019;39(3):172–7.
8. Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet. 2011;377(9773):1276– 87.
9. Tarantino U, Piccirilli E, Fantini M, Baldi J, Gasbarra E, Bei R. Sarcopenia and fragility fractures: molecular and clinical evidence of the bone-muscle interaction. J Bone Joint Surg. 2015;97(5):429–37.
10. Hars M, Biver E, Chevalley T, et al. Low lean mass predicts incident fractures independently from frax: a prospective cohort study of recent retirees. J Bone Miner Res. 2016;31(11):2048–56.
11. Bigham-Sadegh A, Oryan A. Basic concepts regarding fracture healing and the current options and future directions in managing bone fractures. Int Wound J. 2015;12(3):238–47.
12. Wu AM, Bisignano C, James SL, et al. Global, regional, and national burden of bone fractures in 204 countries and territories, 1990–2019: a systematic analysis from the Global Burden of Disease Study 2019. Lancet Healthy Longev. 2021;2(9):e580–92.
13. Ross PD. Clinical consequences of vertebral fractures. Am J Med. 1997;103(2):S30–43.
14. Baertl S, Alt V, Rupp M. Surgical enhancement of fracture healing – operative vs. nonoperative treatment. Injury. 2021;52:S12–7.
15. Perracini MR, Kristensen MT, Cunningham C, Sherrington C. Physiotherapy following fragility fractures. Injury. 2018;49(8):1413–7.
16. Bruder AM, Taylor NF, Dodd KJ, Shields N. Physiotherapy intervention practice patterns used in rehabilitation after distal radial fracture. Physiotherapy. 2013;99(3):233–40.
17. Wakefield AE, McQueen MM. The role of physiotherapy and clinical predictors of outcome after fracture of the distal radius. J Bone Joint Surg. 2000;82(7):972–6.
18. Fischer V, Haffner-Luntzer M, Amling M, Ignatius A. Calcium and vitamin D in bone fracture healing and post-traumatic bone turnover. Eur Cell Mater. 2018;35:365–85.
19. Bodenner D, Redman C, Riggs A. Teriparatide in the management of osteoporosis. Clin Interv Aging. 2007;2(4):499-507.
20. Kates SL, Ackert-Bicknell CL. How do bisphosphonates affect fracture healing? Injury. 2016;47:S65–8. 21. Agarwala S, Vijayvargiya M. Repurposing denosumab for recalcitrant bone healing. BMJ Case Rep. 2021;14(2):e238460.
22. Roy A, Thulasiraman S, Panneerselvam E, et al. Evaluation of the efficacy of salmon calcitonin nasal spray on bone healing following open reduction and internal fixation of mandibular fractures: A randomized controlled trial. J Craniomaxillofac Surg. 2021;49(12):1151–7.
23. Beil FT, Barvencik F, Gebauer M, et al. Effects of Estrogen on Fracture Healing in Mice. J Trauma. 2010;69(5):1259–65.
24. Tahami M, Haddad B, Abtahian A, Hashemi A, Aminian A, Konan S. Potential role of local estrogen in enhancement of fracture healing: preclinical study in rabbits. Arch Bone Jt Surg. 2016;4(4):323–9.
25. Brahmkshatriya H, Shah K, Ananthkumar G, Brahmkshatriya M. Clinical evaluation of Cissus quadrangularis as osteogenic agent in maxillofacial fracture: A pilot study. Ayu. 2015;36(2):169.
26. Maruyama M, Rhee C, Utsunomiya T, et al. Modulation of the inflammatory response and bone healing. Front Endocrinol. 2020;11.
27. Bigham‐Sadegh A, Oryan A. Basic concepts regarding fracture healing and the current options and future directions in managing bone fractures. Int Wound J. 2015;12(3):238–47.
28. Roberts TT, Rosenbaum AJ. Bone grafts, bone substitutes and orthobiologics. Organogenesis. 2012;8(4):114–24.
29. Schell H, Duda GN, Peters A, Tsitsilonis S, Johnson KA, Schmidt-Bleek K. The haematoma and its role in bone healing. J Exp Orthop. 2017;4(1):5.
30. Shiu HT, Leung PC, Ko CH. The roles of cellular and molecular components of a hematoma at early stage of bone healing. J Tissue Eng Regen Med. 2018;12(4):e1911–25.
31. Giannoudis P V., Hak D, Sanders D, Donohoe E, Tosounidis T, Bahney C. Inflammation, bone healing, and anti-inflammatory drugs. J Orthop Trauma. 2015;29(Suppl 12):S6–9.
32. Lin HN, O’Connor JP. Immunohistochemical localization of key arachidonic acid metabolism enzymes during fracture healing in mice. PLoS One. 2014;9(2):e88423.
33. Xie C, Ming X, Wang Q, et al. COX-2 from the injury milieu is critical for the initiation of periosteal progenitor cell mediated bone healing. Bone. 2008;43(6):1075–83.
34. Ren W, Dziak R. Effects of leukotrienes on osteoblastic cell proliferation. Calcif Tissue Int. 1991;49(3):197–201.
35. Schindeler A, McDonald MM, Bokko P, Little DG. Bone remodeling during fracture repair: The cellular picture. Semin Cell Dev Biol. 2008;19(5):459–66.
36. Akino K, Mineda T, Mori N, Hirano A, Imaizumi T, Akita S. Attenuation of cysteinyl leukotrienes induces human mesenchymal stem cell differentiation. Wound Repair Regen. 2006;14(3):343–9.
37. Ford-Hutchinson AW, Gresser M, Young RN. 5-Lipoxygenase. Annu Rev Biochem. 1994;63(1):383–417.
38. Werz O. 5-Lipoxygenase: cellular biology and molecular pharmacology. Curr Drug Targets Inflamm Allergy. 2002;1(1):23–44.
39. Matsumoto T, Funk CD, Rådmark O, Höög JO, Jörnvall H, Samuelsson B. Molecular cloning and amino acid sequence of human 5-lipoxygenase. Proc Natl Acad Sci U S A. 1988;85(1):26–30.
40. Sinha S, Doble M, Manju SL. 5-Lipoxygenase as a drug target: A review on trends in inhibitors structural design, SAR and mechanism based approach. Bioorg Med Chem. 2019;27(17):3745–59.
41. Rask-Madsen J, Bukhave K, Laursen LS, Lauritsen K. 5-Lipoxygenase inhibitors for the treatment of inflammatory bowel disease. Agents Actions. 1992;Spec No:C37-46.
42. Ayola-Serrano NC, Roy N, Fathah Z, et al. The role of 5-lipoxygenase in the pathophysiology of COVID-19 and its therapeutic implications. Inflamm Res. 2021;70(8):877–89.
43. Suva MA, Kheni DB, Sureja VP. Aflapin: A novel and selective 5-lipoxygenase inhibitor for arthritis management. Indian Journal of Pain. 2018;32(1):16.
44. Lee JM, Park H, Noh ALSM, et al. 5-Lipoxygenase Mediates RANKL-Induced osteoclast formation via the cysteinyl leukotriene receptor 1. J Immunol. 2012;189(11):5284–92.
45. Gallwitz WE, Mundy GR, Lee CH, et al. 5-Lipoxygenase metabolites of arachidonic acid stimulate isolated osteoclasts to resorb calcified matrices. J Biol Chem. 1993;268(14):10087–94.
46. Park JH, Lee NK, Lee SY. Current understanding of RANK signaling in osteoclast differentiation and maturation. Mol Cells. 2017;40(10):706–13.
47. Paula-Silva FWG, Petean IBF, da Silva LAB, Faccioli LH. Dual role of 5-lipoxygenase in osteoclastogenesis in bacterial-induced apical periodontitis. J Endod. 2016;42(3):447–54.
48. Lopes DEM, Jabr CL, Dejani NN, et al. Inhibition of 5-Lipoxygenase (5-Lo) attenuates inflammation and bone resorption in lipopolysaccharide (lps)-induced periodontal Disease. J Periodontol. 2017;1–18. 49. Traianedes K, Dallas MR, Garrett IR, Mundy GR, Bonewald LF. 5-Lipoxygenase metabolites inhibit bone formation in Vitro. Endocrinology. 1998;139(7):3178–84.
50. Manigrasso MB, O’Connor JP. Accelerated fracture healing in mice lacking the 5-lipoxygenase gene. Acta Orthop. 2010;81(6):748–55.
51. Wixted JJ, Fanning PJ, Gaur T, et al. Enhanced fracture repair by leukotriene antagonism is characterized by increased chondrocyte proliferation and early bone formation: A novel role of the cysteinyl LT‐1 receptor. J Cell Physiol. 2009;221(1):31–9.
52. Cottrell JA, OʼConnor JP. Pharmacological inhibition of 5-lipoxygenase accelerates and enhances fracture healing. J Bone Joint Surg. 2009;91(11):2653–65.
53. Cottrell JA, Keshav V, Mitchell A, O’Connor JP. Local inhibition of 5-lipoxygenase enhances bone formation in a rat model. Bone Joint Res. 2013;2(2):41–50.
54. Biguetti CC, Couto MCR, Silva ACR, et al. New surgical model for bone–muscle injury reveals age and gender-related healing patterns in the 5 lipoxygenase (5lo) knockout mouse. Front Endocrinol. 2020;11.
55. Saul D, Hohl FE, Franz MK, et al. Inhibition of lipoxygenases showed no benefit for the
musculoskeletal system in estrogen deficient rats. Front Endocrinol. 2021;12.
56. Saul D, Weber M, Zimmermann MH, et al. Effect of the lipoxygenase inhibitor baicalein on bone tissue and bone healing in ovariectomized rats. Nutr Metab. 2019;16(1):4.
57. Bruderer M, Richards R, Alini M, Stoddart M. Role and regulation of runx2 in osteogenesis. Eur Cell Mater. 2014;28:269–86.
58. Komori T. Regulation of proliferation, differentiation and functions of osteoblasts by runx2. Int J Mol Sci. 2019;20(7):1694.
59. Chiu WK, Vien BS, Russ M, Fitzgerald M. Healing assessment of fractured femur treated with an intramedullary nail. Struct Health Monit. 2021;20(3):782–90.
60. Bong MR, Kummer FJ, Koval KJ, Egol KA. Intramedullary nailing of the lower extremity: biomechanics and biology. J Am Acad Orthop Surg. 2007;15(2):97–106.
61. Khazai N, Judd SE, Tangpricha V. Calcium and vitamin D: Skeletal and extraskeletal health. Curr Rheumatol Rep. 2008;10(2):110–7.
62. Muthusami S, Senthilkumar K, Vignesh C, et al. Effects of Cissus quadrangularis on the proliferation, differentiation and matrix mineralization of human osteoblast like SaOS‐2 cells. J Cell Biochem. 2011;112(4):1035–45
Tangpricha V. Calcium and vitamin D: Skeletal and extraskeletal health. Curr Rheumatol Rep. 2008;10(2):110–7.
62. Muthusami S, Senthilkumar K, Vignesh C, et al. Effects of Cissus quadrangularis on the proliferation, differentiation and matrix mineralization of human osteoblast like SaOS‐2 cells. J Cell Biochem. 2011;112(4):1035–45
2. Gerard J. Tortora, Bryan Derrickson. Principles of Anatomy and Physiology. 14th ed. John Wiley & Sons; 2014. p. 169–191.
3. Florencio-Silva R, Sasso GR da S, Sasso-Cerri E, Simões MJ, Cerri PS. Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells. Biomed Res Int. 2015;2015:1–17.
4. Castillo AB, Leucht P. Bone Homeostasis and Repair: Forced Into Shape. Curr Rheumatol Rep. 2015;17(9):58.
5. Mödinger Y, Löffler B, Huber-Lang M, Ignatius A. Complement involvement in bone homeostasis and bone disorders. Semin Immunol. 2018;37:53–65.
6. Ghiasi MS, Chen J, Vaziri A, Rodriguez EK, Nazarian A. Bone fracture healing in mechanobiological modeling: A review of principles and methods. Bone Rep. 2017;6:87–100.
7. Syed MA, Azim SR, Baig M. Frequency of orthopedic problems among patients attending an orthopedic outpatient department: a retrospective analysis of 23 495 cases. Ann Saudi Med. 2019;39(3):172–7.
8. Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet. 2011;377(9773):1276– 87.
9. Tarantino U, Piccirilli E, Fantini M, Baldi J, Gasbarra E, Bei R. Sarcopenia and fragility fractures: molecular and clinical evidence of the bone-muscle interaction. J Bone Joint Surg. 2015;97(5):429–37.
10. Hars M, Biver E, Chevalley T, et al. Low lean mass predicts incident fractures independently from frax: a prospective cohort study of recent retirees. J Bone Miner Res. 2016;31(11):2048–56.
11. Bigham-Sadegh A, Oryan A. Basic concepts regarding fracture healing and the current options and future directions in managing bone fractures. Int Wound J. 2015;12(3):238–47.
12. Wu AM, Bisignano C, James SL, et al. Global, regional, and national burden of bone fractures in 204 countries and territories, 1990–2019: a systematic analysis from the Global Burden of Disease Study 2019. Lancet Healthy Longev. 2021;2(9):e580–92.
13. Ross PD. Clinical consequences of vertebral fractures. Am J Med. 1997;103(2):S30–43.
14. Baertl S, Alt V, Rupp M. Surgical enhancement of fracture healing – operative vs. nonoperative treatment. Injury. 2021;52:S12–7.
15. Perracini MR, Kristensen MT, Cunningham C, Sherrington C. Physiotherapy following fragility fractures. Injury. 2018;49(8):1413–7.
16. Bruder AM, Taylor NF, Dodd KJ, Shields N. Physiotherapy intervention practice patterns used in rehabilitation after distal radial fracture. Physiotherapy. 2013;99(3):233–40.
17. Wakefield AE, McQueen MM. The role of physiotherapy and clinical predictors of outcome after fracture of the distal radius. J Bone Joint Surg. 2000;82(7):972–6.
18. Fischer V, Haffner-Luntzer M, Amling M, Ignatius A. Calcium and vitamin D in bone fracture healing and post-traumatic bone turnover. Eur Cell Mater. 2018;35:365–85.
19. Bodenner D, Redman C, Riggs A. Teriparatide in the management of osteoporosis. Clin Interv Aging. 2007;2(4):499-507.
20. Kates SL, Ackert-Bicknell CL. How do bisphosphonates affect fracture healing? Injury. 2016;47:S65–8. 21. Agarwala S, Vijayvargiya M. Repurposing denosumab for recalcitrant bone healing. BMJ Case Rep. 2021;14(2):e238460.
22. Roy A, Thulasiraman S, Panneerselvam E, et al. Evaluation of the efficacy of salmon calcitonin nasal spray on bone healing following open reduction and internal fixation of mandibular fractures: A randomized controlled trial. J Craniomaxillofac Surg. 2021;49(12):1151–7.
23. Beil FT, Barvencik F, Gebauer M, et al. Effects of Estrogen on Fracture Healing in Mice. J Trauma. 2010;69(5):1259–65.
24. Tahami M, Haddad B, Abtahian A, Hashemi A, Aminian A, Konan S. Potential role of local estrogen in enhancement of fracture healing: preclinical study in rabbits. Arch Bone Jt Surg. 2016;4(4):323–9.
25. Brahmkshatriya H, Shah K, Ananthkumar G, Brahmkshatriya M. Clinical evaluation of Cissus quadrangularis as osteogenic agent in maxillofacial fracture: A pilot study. Ayu. 2015;36(2):169.
26. Maruyama M, Rhee C, Utsunomiya T, et al. Modulation of the inflammatory response and bone healing. Front Endocrinol. 2020;11.
27. Bigham‐Sadegh A, Oryan A. Basic concepts regarding fracture healing and the current options and future directions in managing bone fractures. Int Wound J. 2015;12(3):238–47.
28. Roberts TT, Rosenbaum AJ. Bone grafts, bone substitutes and orthobiologics. Organogenesis. 2012;8(4):114–24.
29. Schell H, Duda GN, Peters A, Tsitsilonis S, Johnson KA, Schmidt-Bleek K. The haematoma and its role in bone healing. J Exp Orthop. 2017;4(1):5.
30. Shiu HT, Leung PC, Ko CH. The roles of cellular and molecular components of a hematoma at early stage of bone healing. J Tissue Eng Regen Med. 2018;12(4):e1911–25.
31. Giannoudis P V., Hak D, Sanders D, Donohoe E, Tosounidis T, Bahney C. Inflammation, bone healing, and anti-inflammatory drugs. J Orthop Trauma. 2015;29(Suppl 12):S6–9.
32. Lin HN, O’Connor JP. Immunohistochemical localization of key arachidonic acid metabolism enzymes during fracture healing in mice. PLoS One. 2014;9(2):e88423.
33. Xie C, Ming X, Wang Q, et al. COX-2 from the injury milieu is critical for the initiation of periosteal progenitor cell mediated bone healing. Bone. 2008;43(6):1075–83.
34. Ren W, Dziak R. Effects of leukotrienes on osteoblastic cell proliferation. Calcif Tissue Int. 1991;49(3):197–201.
35. Schindeler A, McDonald MM, Bokko P, Little DG. Bone remodeling during fracture repair: The cellular picture. Semin Cell Dev Biol. 2008;19(5):459–66.
36. Akino K, Mineda T, Mori N, Hirano A, Imaizumi T, Akita S. Attenuation of cysteinyl leukotrienes induces human mesenchymal stem cell differentiation. Wound Repair Regen. 2006;14(3):343–9.
37. Ford-Hutchinson AW, Gresser M, Young RN. 5-Lipoxygenase. Annu Rev Biochem. 1994;63(1):383–417.
38. Werz O. 5-Lipoxygenase: cellular biology and molecular pharmacology. Curr Drug Targets Inflamm Allergy. 2002;1(1):23–44.
39. Matsumoto T, Funk CD, Rådmark O, Höög JO, Jörnvall H, Samuelsson B. Molecular cloning and amino acid sequence of human 5-lipoxygenase. Proc Natl Acad Sci U S A. 1988;85(1):26–30.
40. Sinha S, Doble M, Manju SL. 5-Lipoxygenase as a drug target: A review on trends in inhibitors structural design, SAR and mechanism based approach. Bioorg Med Chem. 2019;27(17):3745–59.
41. Rask-Madsen J, Bukhave K, Laursen LS, Lauritsen K. 5-Lipoxygenase inhibitors for the treatment of inflammatory bowel disease. Agents Actions. 1992;Spec No:C37-46.
42. Ayola-Serrano NC, Roy N, Fathah Z, et al. The role of 5-lipoxygenase in the pathophysiology of COVID-19 and its therapeutic implications. Inflamm Res. 2021;70(8):877–89.
43. Suva MA, Kheni DB, Sureja VP. Aflapin: A novel and selective 5-lipoxygenase inhibitor for arthritis management. Indian Journal of Pain. 2018;32(1):16.
44. Lee JM, Park H, Noh ALSM, et al. 5-Lipoxygenase Mediates RANKL-Induced osteoclast formation via the cysteinyl leukotriene receptor 1. J Immunol. 2012;189(11):5284–92.
45. Gallwitz WE, Mundy GR, Lee CH, et al. 5-Lipoxygenase metabolites of arachidonic acid stimulate isolated osteoclasts to resorb calcified matrices. J Biol Chem. 1993;268(14):10087–94.
46. Park JH, Lee NK, Lee SY. Current understanding of RANK signaling in osteoclast differentiation and maturation. Mol Cells. 2017;40(10):706–13.
47. Paula-Silva FWG, Petean IBF, da Silva LAB, Faccioli LH. Dual role of 5-lipoxygenase in osteoclastogenesis in bacterial-induced apical periodontitis. J Endod. 2016;42(3):447–54.
48. Lopes DEM, Jabr CL, Dejani NN, et al. Inhibition of 5-Lipoxygenase (5-Lo) attenuates inflammation and bone resorption in lipopolysaccharide (lps)-induced periodontal Disease. J Periodontol. 2017;1–18. 49. Traianedes K, Dallas MR, Garrett IR, Mundy GR, Bonewald LF. 5-Lipoxygenase metabolites inhibit bone formation in Vitro. Endocrinology. 1998;139(7):3178–84.
50. Manigrasso MB, O’Connor JP. Accelerated fracture healing in mice lacking the 5-lipoxygenase gene. Acta Orthop. 2010;81(6):748–55.
51. Wixted JJ, Fanning PJ, Gaur T, et al. Enhanced fracture repair by leukotriene antagonism is characterized by increased chondrocyte proliferation and early bone formation: A novel role of the cysteinyl LT‐1 receptor. J Cell Physiol. 2009;221(1):31–9.
52. Cottrell JA, OʼConnor JP. Pharmacological inhibition of 5-lipoxygenase accelerates and enhances fracture healing. J Bone Joint Surg. 2009;91(11):2653–65.
53. Cottrell JA, Keshav V, Mitchell A, O’Connor JP. Local inhibition of 5-lipoxygenase enhances bone formation in a rat model. Bone Joint Res. 2013;2(2):41–50.
54. Biguetti CC, Couto MCR, Silva ACR, et al. New surgical model for bone–muscle injury reveals age and gender-related healing patterns in the 5 lipoxygenase (5lo) knockout mouse. Front Endocrinol. 2020;11.
55. Saul D, Hohl FE, Franz MK, et al. Inhibition of lipoxygenases showed no benefit for the
musculoskeletal system in estrogen deficient rats. Front Endocrinol. 2021;12.
56. Saul D, Weber M, Zimmermann MH, et al. Effect of the lipoxygenase inhibitor baicalein on bone tissue and bone healing in ovariectomized rats. Nutr Metab. 2019;16(1):4.
57. Bruderer M, Richards R, Alini M, Stoddart M. Role and regulation of runx2 in osteogenesis. Eur Cell Mater. 2014;28:269–86.
58. Komori T. Regulation of proliferation, differentiation and functions of osteoblasts by runx2. Int J Mol Sci. 2019;20(7):1694.
59. Chiu WK, Vien BS, Russ M, Fitzgerald M. Healing assessment of fractured femur treated with an intramedullary nail. Struct Health Monit. 2021;20(3):782–90.
60. Bong MR, Kummer FJ, Koval KJ, Egol KA. Intramedullary nailing of the lower extremity: biomechanics and biology. J Am Acad Orthop Surg. 2007;15(2):97–106.
61. Khazai N, Judd SE,1. Datta HK, Ng WF, Walker JA, Tuck SP, Varanasi SS. The cell biology of bone metabolism. J Clin Pathol. 2008;61(5):577–87.
2. Gerard J. Tortora, Bryan Derrickson. Principles of Anatomy and Physiology. 14th ed. John Wiley & Sons; 2014. p. 169–191.
3. Florencio-Silva R, Sasso GR da S, Sasso-Cerri E, Simões MJ, Cerri PS. Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells. Biomed Res Int. 2015;2015:1–17.
4. Castillo AB, Leucht P. Bone Homeostasis and Repair: Forced Into Shape. Curr Rheumatol Rep. 2015;17(9):58.
5. Mödinger Y, Löffler B, Huber-Lang M, Ignatius A. Complement involvement in bone homeostasis and bone disorders. Semin Immunol. 2018;37:53–65.
6. Ghiasi MS, Chen J, Vaziri A, Rodriguez EK, Nazarian A. Bone fracture healing in mechanobiological modeling: A review of principles and methods. Bone Rep. 2017;6:87–100.
7. Syed MA, Azim SR, Baig M. Frequency of orthopedic problems among patients attending an orthopedic outpatient department: a retrospective analysis of 23 495 cases. Ann Saudi Med. 2019;39(3):172–7.
8. Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet. 2011;377(9773):1276– 87.
9. Tarantino U, Piccirilli E, Fantini M, Baldi J, Gasbarra E, Bei R. Sarcopenia and fragility fractures: molecular and clinical evidence of the bone-muscle interaction. J Bone Joint Surg. 2015;97(5):429–37.
10. Hars M, Biver E, Chevalley T, et al. Low lean mass predicts incident fractures independently from frax: a prospective cohort study of recent retirees. J Bone Miner Res. 2016;31(11):2048–56.
11. Bigham-Sadegh A, Oryan A. Basic concepts regarding fracture healing and the current options and future directions in managing bone fractures. Int Wound J. 2015;12(3):238–47.
12. Wu AM, Bisignano C, James SL, et al. Global, regional, and national burden of bone fractures in 204 countries and territories, 1990–2019: a systematic analysis from the Global Burden of Disease Study 2019. Lancet Healthy Longev. 2021;2(9):e580–92.
13. Ross PD. Clinical consequences of vertebral fractures. Am J Med. 1997;103(2):S30–43.
14. Baertl S, Alt V, Rupp M. Surgical enhancement of fracture healing – operative vs. nonoperative treatment. Injury. 2021;52:S12–7.
15. Perracini MR, Kristensen MT, Cunningham C, Sherrington C. Physiotherapy following fragility fractures. Injury. 2018;49(8):1413–7.
16. Bruder AM, Taylor NF, Dodd KJ, Shields N. Physiotherapy intervention practice patterns used in rehabilitation after distal radial fracture. Physiotherapy. 2013;99(3):233–40.
17. Wakefield AE, McQueen MM. The role of physiotherapy and clinical predictors of outcome after fracture of the distal radius. J Bone Joint Surg. 2000;82(7):972–6.
18. Fischer V, Haffner-Luntzer M, Amling M, Ignatius A. Calcium and vitamin D in bone fracture healing and post-traumatic bone turnover. Eur Cell Mater. 2018;35:365–85.
19. Bodenner D, Redman C, Riggs A. Teriparatide in the management of osteoporosis. Clin Interv Aging. 2007;2(4):499-507.
20. Kates SL, Ackert-Bicknell CL. How do bisphosphonates affect fracture healing? Injury. 2016;47:S65–8. 21. Agarwala S, Vijayvargiya M. Repurposing denosumab for recalcitrant bone healing. BMJ Case Rep. 2021;14(2):e238460.
22. Roy A, Thulasiraman S, Panneerselvam E, et al. Evaluation of the efficacy of salmon calcitonin nasal spray on bone healing following open reduction and internal fixation of mandibular fractures: A randomized controlled trial. J Craniomaxillofac Surg. 2021;49(12):1151–7.
23. Beil FT, Barvencik F, Gebauer M, et al. Effects of Estrogen on Fracture Healing in Mice. J Trauma. 2010;69(5):1259–65.
24. Tahami M, Haddad B, Abtahian A, Hashemi A, Aminian A, Konan S. Potential role of local estrogen in enhancement of fracture healing: preclinical study in rabbits. Arch Bone Jt Surg. 2016;4(4):323–9.
25. Brahmkshatriya H, Shah K, Ananthkumar G, Brahmkshatriya M. Clinical evaluation of Cissus quadrangularis as osteogenic agent in maxillofacial fracture: A pilot study. Ayu. 2015;36(2):169.
26. Maruyama M, Rhee C, Utsunomiya T, et al. Modulation of the inflammatory response and bone healing. Front Endocrinol. 2020;11.
27. Bigham‐Sadegh A, Oryan A. Basic concepts regarding fracture healing and the current options and future directions in managing bone fractures. Int Wound J. 2015;12(3):238–47.
28. Roberts TT, Rosenbaum AJ. Bone grafts, bone substitutes and orthobiologics. Organogenesis. 2012;8(4):114–24.
29. Schell H, Duda GN, Peters A, Tsitsilonis S, Johnson KA, Schmidt-Bleek K. The haematoma and its role in bone healing. J Exp Orthop. 2017;4(1):5.
30. Shiu HT, Leung PC, Ko CH. The roles of cellular and molecular components of a hematoma at early stage of bone healing. J Tissue Eng Regen Med. 2018;12(4):e1911–25.
31. Giannoudis P V., Hak D, Sanders D, Donohoe E, Tosounidis T, Bahney C. Inflammation, bone healing, and anti-inflammatory drugs. J Orthop Trauma. 2015;29(Suppl 12):S6–9.
32. Lin HN, O’Connor JP. Immunohistochemical localization of key arachidonic acid metabolism enzymes during fracture healing in mice. PLoS One. 2014;9(2):e88423.
33. Xie C, Ming X, Wang Q, et al. COX-2 from the injury milieu is critical for the initiation of periosteal progenitor cell mediated bone healing. Bone. 2008;43(6):1075–83.
34. Ren W, Dziak R. Effects of leukotrienes on osteoblastic cell proliferation. Calcif Tissue Int. 1991;49(3):197–201.
35. Schindeler A, McDonald MM, Bokko P, Little DG. Bone remodeling during fracture repair: The cellular picture. Semin Cell Dev Biol. 2008;19(5):459–66.
36. Akino K, Mineda T, Mori N, Hirano A, Imaizumi T, Akita S. Attenuation of cysteinyl leukotrienes induces human mesenchymal stem cell differentiation. Wound Repair Regen. 2006;14(3):343–9.
37. Ford-Hutchinson AW, Gresser M, Young RN. 5-Lipoxygenase. Annu Rev Biochem. 1994;63(1):383–417.
38. Werz O. 5-Lipoxygenase: cellular biology and molecular pharmacology. Curr Drug Targets Inflamm Allergy. 2002;1(1):23–44.
39. Matsumoto T, Funk CD, Rådmark O, Höög JO, Jörnvall H, Samuelsson B. Molecular cloning and amino acid sequence of human 5-lipoxygenase. Proc Natl Acad Sci U S A. 1988;85(1):26–30.
40. Sinha S, Doble M, Manju SL. 5-Lipoxygenase as a drug target: A review on trends in inhibitors structural design, SAR and mechanism based approach. Bioorg Med Chem. 2019;27(17):3745–59.
41. Rask-Madsen J, Bukhave K, Laursen LS, Lauritsen K. 5-Lipoxygenase inhibitors for the treatment of inflammatory bowel disease. Agents Actions. 1992;Spec No:C37-46.
42. Ayola-Serrano NC, Roy N, Fathah Z, et al. The role of 5-lipoxygenase in the pathophysiology of COVID-19 and its therapeutic implications. Inflamm Res. 2021;70(8):877–89.
43. Suva MA, Kheni DB, Sureja VP. Aflapin: A novel and selective 5-lipoxygenase inhibitor for arthritis management. Indian Journal of Pain. 2018;32(1):16.
44. Lee JM, Park H, Noh ALSM, et al. 5-Lipoxygenase Mediates RANKL-Induced osteoclast formation via the cysteinyl leukotriene receptor 1. J Immunol. 2012;189(11):5284–92.
45. Gallwitz WE, Mundy GR, Lee CH, et al. 5-Lipoxygenase metabolites of arachidonic acid stimulate isolated osteoclasts to resorb calcified matrices. J Biol Chem. 1993;268(14):10087–94.
46. Park JH, Lee NK, Lee SY. Current understanding of RANK signaling in osteoclast differentiation and maturation. Mol Cells. 2017;40(10):706–13.
47. Paula-Silva FWG, Petean IBF, da Silva LAB, Faccioli LH. Dual role of 5-lipoxygenase in osteoclastogenesis in bacterial-induced apical periodontitis. J Endod. 2016;42(3):447–54.
48. Lopes DEM, Jabr CL, Dejani NN, et al. Inhibition of 5-Lipoxygenase (5-Lo) attenuates inflammation and bone resorption in lipopolysaccharide (lps)-induced periodontal Disease. J Periodontol. 2017;1–18. 49. Traianedes K, Dallas MR, Garrett IR, Mundy GR, Bonewald LF. 5-Lipoxygenase metabolites inhibit bone formation in Vitro. Endocrinology. 1998;139(7):3178–84.
50. Manigrasso MB, O’Connor JP. Accelerated fracture healing in mice lacking the 5-lipoxygenase gene. Acta Orthop. 2010;81(6):748–55.
51. Wixted JJ, Fanning PJ, Gaur T, et al. Enhanced fracture repair by leukotriene antagonism is characterized by increased chondrocyte proliferation and early bone formation: A novel role of the cysteinyl LT‐1 receptor. J Cell Physiol. 2009;221(1):31–9.
52. Cottrell JA, OʼConnor JP. Pharmacological inhibition of 5-lipoxygenase accelerates and enhances fracture healing. J Bone Joint Surg. 2009;91(11):2653–65.
53. Cottrell JA, Keshav V, Mitchell A, O’Connor JP. Local inhibition of 5-lipoxygenase enhances bone formation in a rat model. Bone Joint Res. 2013;2(2):41–50.
54. Biguetti CC, Couto MCR, Silva ACR, et al. New surgical model for bone–muscle injury reveals age and gender-related healing patterns in the 5 lipoxygenase (5lo) knockout mouse. Front Endocrinol. 2020;11.
55. Saul D, Hohl FE, Franz MK, et al. Inhibition of lipoxygenases showed no benefit for the
musculoskeletal system in estrogen deficient rats. Front Endocrinol. 2021;12.
56. Saul D, Weber M, Zimmermann MH, et al. Effect of the lipoxygenase inhibitor baicalein on bone tissue and bone healing in ovariectomized rats. Nutr Metab. 2019;16(1):4.
57. Bruderer M, Richards R, Alini M, Stoddart M. Role and regulation of runx2 in osteogenesis. Eur Cell Mater. 2014;28:269–86.
58. Komori T. Regulation of proliferation, differentiation and functions of osteoblasts by runx2. Int J Mol Sci. 2019;20(7):1694.
59. Chiu WK, Vien BS, Russ M, Fitzgerald M. Healing assessment of fractured femur treated with an intramedullary nail. Struct Health Monit. 2021;20(3):782–90.
60. Bong MR, Kummer FJ, Koval KJ, Egol KA. Intramedullary nailing of the lower extremity: biomechanics and biology. J Am Acad Orthop Surg. 2007;15(2):97–106.
61. Khazai N, Judd SE, Tangpricha V. Calcium and vitamin D: Skeletal and extraskeletal health. Curr Rheumatol Rep. 2008;10(2):110–7.
62. Muthusami S, Senthilkumar K, Vignesh C, et al. Effects of Cissus quadrangularis on the proliferation, differentiation and matrix mineralization of human osteoblast like SaOS‐2 cells. J Cell Biochem. 2011;112(4):1035–45
1. Datta HK, Ng WF, Walker JA, Tuck SP, Varanasi SS. The cell biology of bone metabolism. J Clin Pathol. 2008;61(5):577–87.
2. Gerard J. Tortora, Bryan Derrickson. Principles of Anatomy and Physiology. 14th ed. John Wiley & Sons; 2014. p. 169–191.
3. Florencio-Silva R, Sasso GR da S, Sasso-Cerri E, Simões MJ, Cerri PS. Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells. Biomed Res Int. 2015;2015:1–17.
4. Castillo AB, Leucht P. Bone Homeostasis and Repair: Forced Into Shape. Curr Rheumatol Rep. 2015;17(9):58.
5. Mödinger Y, Löffler B, Huber-Lang M, Ignatius A. Complement involvement in bone homeostasis and bone disorders. Semin Immunol. 2018;37:53–65.
6. Ghiasi MS, Chen J, Vaziri A, Rodriguez EK, Nazarian A. Bone fracture healing in mechanobiological modeling: A review of principles and methods. Bone Rep. 2017;6:87–100.
7. Syed MA, Azim SR, Baig M. Frequency of orthopedic problems among patients attending an orthopedic outpatient department: a retrospective analysis of 23 495 cases. Ann Saudi Med. 2019;39(3):172–7.
8. Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet. 2011;377(9773):1276– 87.
9. Tarantino U, Piccirilli E, Fantini M, Baldi J, Gasbarra E, Bei R. Sarcopenia and fragility fractures: molecular and clinical evidence of the bone-muscle interaction. J Bone Joint Surg. 2015;97(5):429–37.
10. Hars M, Biver E, Chevalley T, et al. Low lean mass predicts incident fractures independently from frax: a prospective cohort study of recent retirees. J Bone Miner Res. 2016;31(11):2048–56.
11. Bigham-Sadegh A, Oryan A. Basic concepts regarding fracture healing and the current options and future directions in managing bone fractures. Int Wound J. 2015;12(3):238–47.
12. Wu AM, Bisignano C, James SL, et al. Global, regional, and national burden of bone fractures in 204 countries and territories, 1990–2019: a systematic analysis from the Global Burden of Disease Study 2019. Lancet Healthy Longev. 2021;2(9):e580–92.
13. Ross PD. Clinical consequences of vertebral fractures. Am J Med. 1997;103(2):S30–43.
14. Baertl S, Alt V, Rupp M. Surgical enhancement of fracture healing – operative vs. nonoperative treatment. Injury. 2021;52:S12–7.
15. Perracini MR, Kristensen MT, Cunningham C, Sherrington C. Physiotherapy following fragility fractures. Injury. 2018;49(8):1413–7.
16. Bruder AM, Taylor NF, Dodd KJ, Shields N. Physiotherapy intervention practice patterns used in rehabilitation after distal radial fracture. Physiotherapy. 2013;99(3):233–40.
17. Wakefield AE, McQueen MM. The role of physiotherapy and clinical predictors of outcome after fracture of the distal radius. J Bone Joint Surg. 2000;82(7):972–6.
18. Fischer V, Haffner-Luntzer M, Amling M, Ignatius A. Calcium and vitamin D in bone fracture healing and post-traumatic bone turnover. Eur Cell Mater. 2018;35:365–85.
19. Bodenner D, Redman C, Riggs A. Teriparatide in the management of osteoporosis. Clin Interv Aging. 2007;2(4):499-507.
20. Kates SL, Ackert-Bicknell CL. How do bisphosphonates affect fracture healing? Injury. 2016;47:S65–8. 21. Agarwala S, Vijayvargiya M. Repurposing denosumab for recalcitrant bone healing. BMJ Case Rep. 2021;14(2):e238460.
22. Roy A, Thulasiraman S, Panneerselvam E, et al. Evaluation of the efficacy of salmon calcitonin nasal spray on bone healing following open reduction and internal fixation of mandibular fractures: A randomized controlled trial. J Craniomaxillofac Surg. 2021;49(12):1151–7.
23. Beil FT, Barvencik F, Gebauer M, et al. Effects of Estrogen on Fracture Healing in Mice. J Trauma. 2010;69(5):1259–65.
24. Tahami M, Haddad B, Abtahian A, Hashemi A, Aminian A, Konan S. Potential role of local estrogen in enhancement of fracture healing: preclinical study in rabbits. Arch Bone Jt Surg. 2016;4(4):323–9.
25. Brahmkshatriya H, Shah K, Ananthkumar G, Brahmkshatriya M. Clinical evaluation of Cissus quadrangularis as osteogenic agent in maxillofacial fracture: A pilot study. Ayu. 2015;36(2):169.
26. Maruyama M, Rhee C, Utsunomiya T, et al. Modulation of the inflammatory response and bone healing. Front Endocrinol. 2020;11.
27. Bigham‐Sadegh A, Oryan A. Basic concepts regarding fracture healing and the current options and future directions in managing bone fractures. Int Wound J. 2015;12(3):238–47.
28. Roberts TT, Rosenbaum AJ. Bone grafts, bone substitutes and orthobiologics. Organogenesis. 2012;8(4):114–24.
29. Schell H, Duda GN, Peters A, Tsitsilonis S, Johnson KA, Schmidt-Bleek K. The haematoma and its role in bone healing. J Exp Orthop. 2017;4(1):5.
30. Shiu HT, Leung PC, Ko CH. The roles of cellular and molecular components of a hematoma at early stage of bone healing. J Tissue Eng Regen Med. 2018;12(4):e1911–25.
31. Giannoudis P V., Hak D, Sanders D, Donohoe E, Tosounidis T, Bahney C. Inflammation, bone healing, and anti-inflammatory drugs. J Orthop Trauma. 2015;29(Suppl 12):S6–9.
32. Lin HN, O’Connor JP. Immunohistochemical localization of key arachidonic acid metabolism enzymes during fracture healing in mice. PLoS One. 2014;9(2):e88423.
33. Xie C, Ming X, Wang Q, et al. COX-2 from the injury milieu is critical for the initiation of periosteal progenitor cell mediated bone healing. Bone. 2008;43(6):1075–83.
34. Ren W, Dziak R. Effects of leukotrienes on osteoblastic cell proliferation. Calcif Tissue Int. 1991;49(3):197–201.
35. Schindeler A, McDonald MM, Bokko P, Little DG. Bone remodeling during fracture repair: The cellular picture. Semin Cell Dev Biol. 2008;19(5):459–66.
36. Akino K, Mineda T, Mori N, Hirano A, Imaizumi T, Akita S. Attenuation of cysteinyl leukotrienes induces human mesenchymal stem cell differentiation. Wound Repair Regen. 2006;14(3):343–9.
37. Ford-Hutchinson AW, Gresser M, Young RN. 5-Lipoxygenase. Annu Rev Biochem. 1994;63(1):383–417.
38. Werz O. 5-Lipoxygenase: cellular biology and molecular pharmacology. Curr Drug Targets Inflamm Allergy. 2002;1(1):23–44.
39. Matsumoto T, Funk CD, Rådmark O, Höög JO, Jörnvall H, Samuelsson B. Molecular cloning and amino acid sequence of human 5-lipoxygenase. Proc Natl Acad Sci U S A. 1988;85(1):26–30.
40. Sinha S, Doble M, Manju SL. 5-Lipoxygenase as a drug target: A review on trends in inhibitors structural design, SAR and mechanism based approach. Bioorg Med Chem. 2019;27(17):3745–59.
41. Rask-Madsen J, Bukhave K, Laursen LS, Lauritsen K. 5-Lipoxygenase inhibitors for the treatment of inflammatory bowel disease. Agents Actions. 1992;Spec No:C37-46.
42. Ayola-Serrano NC, Roy N, Fathah Z, et al. The role of 5-lipoxygenase in the pathophysiology of COVID-19 and its therapeutic implications. Inflamm Res. 2021;70(8):877–89.
43. Suva MA, Kheni DB, Sureja VP. Aflapin: A novel and selective 5-lipoxygenase inhibitor for arthritis management. Indian Journal of Pain. 2018;32(1):16.
44. Lee JM, Park H, Noh ALSM, et al. 5-Lipoxygenase Mediates RANKL-Induced osteoclast formation via the cysteinyl leukotriene receptor 1. J Immunol. 2012;189(11):5284–92.
45. Gallwitz WE, Mundy GR, Lee CH, et al. 5-Lipoxygenase metabolites of arachidonic acid stimulate isolated osteoclasts to resorb calcified matrices. J Biol Chem. 1993;268(14):10087–94.
46. Park JH, Lee NK, Lee SY. Current understanding of RANK signaling in osteoclast differentiation and maturation. Mol Cells. 2017;40(10):706–13.
47. Paula-Silva FWG, Petean IBF, da Silva LAB, Faccioli LH. Dual role of 5-lipoxygenase in osteoclastogenesis in bacterial-induced apical periodontitis. J Endod. 2016;42(3):447–54.
48. Lopes DEM, Jabr CL, Dejani NN, et al. Inhibition of 5-Lipoxygenase (5-Lo) attenuates inflammation and bone resorption in lipopolysaccharide (lps)-induced periodontal Disease. J Periodontol. 2017;1–18. 49. Traianedes K, Dallas MR, Garrett IR, Mundy GR, Bonewald LF. 5-Lipoxygenase metabolites inhibit bone formation in Vitro. Endocrinology. 1998;139(7):3178–84.
50. Manigrasso MB, O’Connor JP. Accelerated fracture healing in mice lacking the 5-lipoxygenase gene. Acta Orthop. 2010;81(6):748–55.
51. Wixted JJ, Fanning PJ, Gaur T, et al. Enhanced fracture repair by leukotriene antagonism is characterized by increased chondrocyte proliferation and early bone formation: A novel role of the cysteinyl LT‐1 receptor. J Cell Physiol. 2009;221(1):31–9.
52. Cottrell JA, OʼConnor JP. Pharmacological inhibition of 5-lipoxygenase accelerates and enhances fracture healing. J Bone Joint Surg. 2009;91(11):2653–65.
53. Cottrell JA, Keshav V, Mitchell A, O’Connor JP. Local inhibition of 5-lipoxygenase enhances bone formation in a rat model. Bone Joint Res. 2013;2(2):41–50.
54. Biguetti CC, Couto MCR, Silva ACR, et al. New surgical model for bone–muscle injury reveals age and gender-related healing patterns in the 5 lipoxygenase (5lo) knockout mouse. Front Endocrinol. 2020;11.
55. Saul D, Hohl FE, Franz MK, et al. Inhibition of lipoxygenases showed no benefit for the
musculoskeletal system in estrogen deficient rats. Front Endocrinol. 2021;12.
56. Saul D, Weber M, Zimmermann MH, et al. Effect of the lipoxygenase inhibitor baicalein on bone tissue and bone healing in ovariectomized rats. Nutr Metab. 2019;16(1):4.
57. Bruderer M, Richards R, Alini M, Stoddart M. Role and regulation of runx2 in osteogenesis. Eur Cell Mater. 2014;28:269–86.
58. Komori T. Regulation of proliferation, differentiation and functions of osteoblasts by runx2. Int J Mol Sci. 2019;20(7):1694.
59. Chiu WK, Vien BS, Russ M, Fitzgerald M. Healing assessment of fractured femur treated with an intramedullary nail. Struct Health Monit. 2021;20(3):782–90.
60. Bong MR, Kummer FJ, Koval KJ, Egol KA. Intramedullary nailing of the lower extremity: biomechanics and biology. J Am Acad Orthop Surg. 2007;15(2):97–106.
61. Khazai N, Judd SE, Tangpricha V. Calcium and vitamin D: Skeletal and extraskeletal health. Curr Rheumatol Rep. 2008;10(2):110–7.
62. Muthusami S, Senthilkumar K, Vignesh C, et al. Effects of Cissus quadrangularis on the proliferation, differentiation and matrix mineralization of human osteoblast like SaOS‐2 cells. J Cell Biochem. 2011;112(4):1035–45
Tangpricha V. Calcium and vitamin D: Skeletal and extraskeletal health. Curr Rheumatol Rep. 2008;10(2):110–7.
62. Muthusami S, Senthilkumar K, Vignesh C, et al. Effects of Cissus quadrangularis on the proliferation, differentiation and matrix mineralization of human osteoblast like SaOS‐2 cells. J Cell Biochem. 2011;112(4):1035–45
| Files | ||
| Issue | Vol 12, No 2 (Spring 2024) | |
| Section | Review Article(s) | |
| DOI | https://doi.org/10.18502/jpc.v12i2.16190 | |
| Keywords | ||
| Lipoxygenase Bone fracture Leukotrienes Osteoclasts Osteoblasts | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Kansagra J, Dubey V, Kheni D, Sureja V. 5-Lipoxygenase: The Therapeutically Unexplored Target for Bone Health. J Pharm Care. 2024;12(2):119-130.
