Research progress of immune cells regulating the occurrence and development of osteonecrosis of the femoral head_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

CAI Lijun , WANG Qiuru , CHEN Changjun ,  KANG Pengde

Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P. R. China;

Corresponding author：

KANG Pengde, Email: kangpd@163.com

Keywords：

Osteonecrosis of the femoral head; immune cells; immune regulation

DOI：

10.7507/1002-1892.202204106

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the characteristics of the occurrence and development of osteonecrosis of the femoral head (ONFH), and to review the important regulatory role of immune cells in the progression of ONFH. Methods The domestic and foreign literature on the immune regulation of ONFH was reviewed, and the relationship between immune cells and the occurrence and development of ONFH was analyzed. Results The ONFH region has a chronic inflammatory reaction and an imbalance between osteoblast and osteoclast, while innate immune cells such as macrophages, neutrophils, dendritic cells, and immune effector cells such as T cells and B cells are closely related to the maintenance of bone homeostasis. Conclusion Immunotherapy targeting the immune cells in the ONFH region and the key factors and proteins in their regulatory pathways may be a feasible method to delay the occurrence, development, and even reverse the pathology of ONFH.

Citation： CAI Lijun, WANG Qiuru, CHEN Changjun, KANG Pengde. Research progress of immune cells regulating the occurrence and development of osteonecrosis of the femoral head. Chinese Journal of Reparative and Reconstructive Surgery, 2022, 36(11): 1428-1433. doi: 10.7507/1002-1892.202204106 Copy

1.	Zhao D, Zhang F, Wang B, et al. Guidelines for clinical diagnosis and treatment of osteonecrosis of the femoral head in adults (2019 version). J Orthop Translat, 2020, 21: 100-110.
2.	Zhang H, Xiao F, Liu Y, et al. A higher frequency of peripheral blood activated B cells in patients with non-traumatic osteonecrosis of the femoral head. Int Immunopharmacol, 2014, 20(1): 95-100.
3.	Wang P, Wang C, Meng H, et al. The role of structural deterioration and biomechanical changes of the necrotic lesion in collapse mechanism of osteonecrosis of the femoral head. Orthop Surg, 2022, 14(5): 831-839.
4.	Mont MA, Salem HS, Piuzzi NS, et al. Nontraumatic osteonecrosis of the femoral head: Where do we stand today?: A 5-year update. J Bone Joint Surg (Am), 2020, 102(12): 1084-1099.
5.	Tan B, Li W, Zeng P, et al. Epidemiological study based on China osteonecrosis of the femoral head database. Orthop Surg, 2021, 13(1): 153-160.
6.	Cui Q, Jo WL, Koo KH, et al. ARCO consensus on the pathogenesis of non-traumatic osteonecrosis of the femoral head. J Korean Med Sci, 2021, 36(10): e65. doi: 10.3346/jkms.2021.36.e65.
7.	Jiang J, Liu X, Lai B, et al. Correlational analysis between neutrophil granulocyte levels and osteonecrosis of the femoral head. BMC Musculoskelet Disord, 2019, 20(1): 393. doi: 10.1186/s12891-019-2778-7.
8.	Wang T, Azeddine B, Mah W, et al. Osteonecrosis of the femoral head: genetic basis. Int Orthop, 2019, 43(3): 519-530.
9.	Gangji V, Soyfoo MS, Heuschling A, et al. Non traumatic osteonecrosis of the femoral head is associated with low bone mass. Bone, 2018, 107: 88-92.
10.	Chang C, Greenspan A, Gershwin ME. The pathogenesis, diagnosis and clinical manifestations of steroid-induced osteonecrosis. J Autoimmun, 2020, 110: 102460. doi: 10.1016/j.jaut.2020.102460.
11.	Hines JT, Jo WL, Cui Q, et al. Osteonecrosis of the femoral head: an updated review of ARCO on pathogenesis, staging and treatment. J Korean Med Sci, 2021, 36(24): e177. doi: 10.3346/jkms.2021.36.e177.
12.	Ma J, Ge J, Gao F, et al. The role of immune regulatory cells in nontraumatic osteonecrosis of the femoral head: A retrospective clinical study. Biomed Res Int, 2019, 2019: 1302015. doi: 10.1155/2019/1302015.
13.	Ma M, Tan Z, Li W, et al. Infographic: Osteoimmunology mechanism of osteonecrosis of the femoral head. Bone Joint Res, 2022, 11(1): 29-31.
14.	Dar HY, Azam Z, Anupam R, et al. Osteoimmunology: The Nexus between bone and immune system. Front Biosci (Landmark Ed), 2018, 23(3): 464-492.
15.	Maeda K, Kobayashi Y, Koide M, et al. The regulation of bone metabolism and disorders by Wnt signaling. Int J Mol Sci, 2019, 20(22): 5525. doi: 10.3390/ijms20225525.
16.	Jiang C, Zhou Z, Lin Y, et al. Astragaloside Ⅳ ameliorates steroid-induced osteonecrosis of the femoral head by repolarizing the phenotype of pro-inflammatory macrophages. Int Immunopharmacol, 2021, 93: 107345. doi: 10.1016/j.intimp.2020.107345.
17.	Jin S, Meng C, He Y, et al. Curcumin prevents osteocyte apoptosis by inhibiting M1-type macrophage polarization in mice model of glucocorticoid-associated osteonecrosis of the femoral head. J Orthop Res, 2020, 38(9): 2020-2030.
18.	Okamoto K, Takayanagi H. Osteoimmunology. Cold Spring Harb Perspect Med, 2019, 9(1): 1-28.
19.	Tsukasaki M, Takayanagi H. Osteoimmunology: evolving concepts in bone-immune interactions in health and disease. Nat Rev Immunol, 2019, 19(10): 626-642.
20.	Kim JM, Lin C, Stavre Z, et al. Osteoblast-osteoclast communi-cation and bone homeostasis. Cells, 2020, 9(9): 2073. doi: 10.3390/cells9092073.
21.	Ma M, Tan Z, Li W, et al. Osteoimmunology and osteonecrosis of the femoral head. Bone Joint Res, 2022, 11(1): 26-28.
22.	Tao J, Dong B, Yang LX, et al. TGF-β₁ expression in adults with non-traumatic osteonecrosis of the femoral head. Mol Med Rep, 2017, 16(6): 9539-9544.
23.	Zhu D, Yu H, Liu P, et al. Calycosin modulates inflammation via suppressing TLR4/NF-κB pathway and promotes bone formation to ameliorate glucocorticoid-induced osteonecrosis of the femoral head in rat. Phytother Res, 2021. doi: 10.1002/ptr.7028.
24.	Deng Z, Ren Y, Park MS, et al. Damage associated molecular patterns in necrotic femoral head inhibit osteogenesis and promote fibrogenesis of mesenchymal stem cells. Bone, 2022, 154: 116215. doi: 10.1016/j.bone.2021.116215.
25.	Adapala NS, Yamaguchi R, Phipps M, et al. Necrotic bone stimulates proinflammatory responses in macrophages through the activation of toll-like receptor 4. Am J Pathol, 2016, 186(11): 2987-2999.
26.	Locati M, Curtale G, Mantovani A. Diversity, mechanisms, and significance of macrophage plasticity. Annu Rev Pathol, 2020, 15: 123-147.
27.	Jin T, Zhang Y, Sun Y, et al. IL-4 gene polymorphisms and their relation to steroid-induced osteonecrosis of the femoral head in Chinese population. Mol Genet Genomic Med, 2019, 7(3): e563. doi: 10.1002/mgg3.563.
28.	von Kaeppler EP, Wang Q, Raghu H, et al. Interleukin 4 promotes anti-inflammatory macrophages that clear cartilage debris and inhibits osteoclast development to protect against osteoarthritis. Clin Immunol, 2021, 229: 108784. doi: 10.1016/j.clim.2021.108784.
29.	Tian G, Liu C, Gong Q, et al. Human umbilical cord mesenchymal stem cells improve the necrosis and osteocyte apoptosis in glucocorticoid-induced osteonecrosis of the femoral head model through reducing the macrophage polarization. Int J Stem Cells, 2022, 15(2): 195-202.
30.	Gkouveris I, Soundia A, Gouveris P, et al. Macrophage involvement in medication-related osteonecrosis of the jaw (MRONJ): A comprehensive, short review. Cancers (Basel), 2022, 14(2): 330. doi: 10.3390/cancers14020330.
31.	Poubelle PE, Chakravarti A, Fernandes MJ, et al. Differential expression of RANK, RANK-L, and osteoprotegerin by synovial fluid neutrophils from patients with rheumatoid arthritis and by healthy human blood neutrophils. Arthritis Res Ther, 2007, 9(2): R25. doi: 10.1186/ar2137.
32.	Yang N, Liu Y. The Role of the immune microenvironment in bone regeneration. Int J Med Sci, 2021, 18(16): 3697-3707.
33.	Dömer D, Walther T, Möller S, et al. Neutrophil extracellular traps activate proinflammatory functions of human neutrophils. Front Immunol, 2021, 12: 636954. doi: 10.3389/fimmu.2021.636954.
34.	Nonokawa M, Shimizu T, Yoshinari M, et al. Association of neutrophil extracellular traps with the development of idiopathic osteonecrosis of the femoral head. Am J Pathol, 2020, 190(11): 2282-2289.
35.	Vitkov L, Minnich B, Knopf J, et al. NETs are double-edged swords with the potential to aggravate or resolve periodontal inflammation. Cells, 2020, 9(12): 2614. doi: 10.3390/cells9122614.
36.	Collin M, Bigley V. Human dendritic cell subsets: an update. Immunology, 2018, 154(1): 3-20.
37.	Elsayed R, Kurago Z, Cutler CW, et al. Role of dendritic cell-mediated immune response in oral homeostasis: A new mechanism of osteonecrosis of the jaw. FASEB J, 2020, 34(2): 2595-2608.
38.	Wang B, Dong Y, Tian Z, et al. The role of dendritic cells derived osteoclasts in bone destruction diseases. Genes Dis, 2020, 8(4): 401-411.
39.	Dong C. Cytokine regulation and function in T cells. Annu Rev Immunol, 2021, 39: 51-76.
40.	Wang X, Chen X, Lu L, et al. Alcoholism and osteoimmunology. Curr Med Chem, 2021, 28(9): 1815-1828.
41.	Fischer V, Haffner-Luntzer M. Interaction between bone and immune cells: Implications for postmenopausal osteoporosis. Semin Cell Dev Biol, 2022, 123: 14-21.
42.	Ono T, Hayashi M, Sasaki F, et al. RANKL biology: bone metabolism, the immune system, and beyond. Inflamm Regen, 2020, 40: 2. doi: 10.1186/s41232-019-0111-3.
43.	Deng Z, Zhang Q, Zhao Z, et al. Crosstalk between immune cells and bone cells or chondrocytes. Int Immunopharmacol, 2021, 101(Pt A): 108179. doi: 10.1016/j.intimp.2021.108179.
44.	Alvarez C, Suliman S, Almarhoumi R, et al. Regulatory T cell phenotype and anti-osteoclastogenic function in experimental periodontitis. Sci Rep, 2020, 10(1): 19018. doi: 10.1038/s41598-020-76038-w.
45.	Lee DSW, Rojas OL, Gommerman JL. B cell depletion therapies in autoimmune disease: advances and mechanistic insights. Nat Rev Drug Discov, 2021, 20(3): 179-199.
46.	Yu R, Zhang J, Zhuo Y, et al. ARG2, MAP4K5 and TSTA3 as diagnostic markers of steroid-induced osteonecrosis of the femoral head and their correlation with immune infiltration. Front Genet, 2021, 12: 691465. doi: 10.3389/fgene.2021.691465.
47.	Wang Y, Liu J, Burrows PD, et al. B cell development and maturation. Adv Exp Med Biol, 2020, 1254: 1-22.
48.	Yoshimoto M. The ontogeny of murine B-1a cells. Int J Hematol, 2020, 111(5): 622-627.
49.	Aziz M, Brenner M, Wang P. Therapeutic potential of B-1a cells in COVID-19. Shock, 2020, 54(5): 586-594.
50.	Weitzmann MN. Bone and the immune system. Toxicol Pathol, 2017, 45(7): 911-924.
51.	Yasuda H. Discovery of the RANKL/RANK/OPG system. J Bone Miner Metab, 2021, 39(1): 2-11.
52.	Han YK, Jin Y, Miao YB, et al. Improved RANKL production by memory B cells: A way for B cells promote alveolar bone destruction during periodontitis. Int Immunopharmacol, 2018, 64: 232-237.

1. Zhao D, Zhang F, Wang B, et al. Guidelines for clinical diagnosis and treatment of osteonecrosis of the femoral head in adults (2019 version). J Orthop Translat, 2020, 21: 100-110.
2. Zhang H, Xiao F, Liu Y, et al. A higher frequency of peripheral blood activated B cells in patients with non-traumatic osteonecrosis of the femoral head. Int Immunopharmacol, 2014, 20(1): 95-100.
3. Wang P, Wang C, Meng H, et al. The role of structural deterioration and biomechanical changes of the necrotic lesion in collapse mechanism of osteonecrosis of the femoral head. Orthop Surg, 2022, 14(5): 831-839.
4. Mont MA, Salem HS, Piuzzi NS, et al. Nontraumatic osteonecrosis of the femoral head: Where do we stand today?: A 5-year update. J Bone Joint Surg (Am), 2020, 102(12): 1084-1099.
5. Tan B, Li W, Zeng P, et al. Epidemiological study based on China osteonecrosis of the femoral head database. Orthop Surg, 2021, 13(1): 153-160.
6. Cui Q, Jo WL, Koo KH, et al. ARCO consensus on the pathogenesis of non-traumatic osteonecrosis of the femoral head. J Korean Med Sci, 2021, 36(10): e65. doi: 10.3346/jkms.2021.36.e65.
7. Jiang J, Liu X, Lai B, et al. Correlational analysis between neutrophil granulocyte levels and osteonecrosis of the femoral head. BMC Musculoskelet Disord, 2019, 20(1): 393. doi: 10.1186/s12891-019-2778-7.
8. Wang T, Azeddine B, Mah W, et al. Osteonecrosis of the femoral head: genetic basis. Int Orthop, 2019, 43(3): 519-530.
9. Gangji V, Soyfoo MS, Heuschling A, et al. Non traumatic osteonecrosis of the femoral head is associated with low bone mass. Bone, 2018, 107: 88-92.
10. Chang C, Greenspan A, Gershwin ME. The pathogenesis, diagnosis and clinical manifestations of steroid-induced osteonecrosis. J Autoimmun, 2020, 110: 102460. doi: 10.1016/j.jaut.2020.102460.
11. Hines JT, Jo WL, Cui Q, et al. Osteonecrosis of the femoral head: an updated review of ARCO on pathogenesis, staging and treatment. J Korean Med Sci, 2021, 36(24): e177. doi: 10.3346/jkms.2021.36.e177.
12. Ma J, Ge J, Gao F, et al. The role of immune regulatory cells in nontraumatic osteonecrosis of the femoral head: A retrospective clinical study. Biomed Res Int, 2019, 2019: 1302015. doi: 10.1155/2019/1302015.
13. Ma M, Tan Z, Li W, et al. Infographic: Osteoimmunology mechanism of osteonecrosis of the femoral head. Bone Joint Res, 2022, 11(1): 29-31.
14. Dar HY, Azam Z, Anupam R, et al. Osteoimmunology: The Nexus between bone and immune system. Front Biosci (Landmark Ed), 2018, 23(3): 464-492.
15. Maeda K, Kobayashi Y, Koide M, et al. The regulation of bone metabolism and disorders by Wnt signaling. Int J Mol Sci, 2019, 20(22): 5525. doi: 10.3390/ijms20225525.
16. Jiang C, Zhou Z, Lin Y, et al. Astragaloside Ⅳ ameliorates steroid-induced osteonecrosis of the femoral head by repolarizing the phenotype of pro-inflammatory macrophages. Int Immunopharmacol, 2021, 93: 107345. doi: 10.1016/j.intimp.2020.107345.
17. Jin S, Meng C, He Y, et al. Curcumin prevents osteocyte apoptosis by inhibiting M1-type macrophage polarization in mice model of glucocorticoid-associated osteonecrosis of the femoral head. J Orthop Res, 2020, 38(9): 2020-2030.
18. Okamoto K, Takayanagi H. Osteoimmunology. Cold Spring Harb Perspect Med, 2019, 9(1): 1-28.
19. Tsukasaki M, Takayanagi H. Osteoimmunology: evolving concepts in bone-immune interactions in health and disease. Nat Rev Immunol, 2019, 19(10): 626-642.
20. Kim JM, Lin C, Stavre Z, et al. Osteoblast-osteoclast communi-cation and bone homeostasis. Cells, 2020, 9(9): 2073. doi: 10.3390/cells9092073.
21. Ma M, Tan Z, Li W, et al. Osteoimmunology and osteonecrosis of the femoral head. Bone Joint Res, 2022, 11(1): 26-28.
22. Tao J, Dong B, Yang LX, et al. TGF-β₁ expression in adults with non-traumatic osteonecrosis of the femoral head. Mol Med Rep, 2017, 16(6): 9539-9544.
23. Zhu D, Yu H, Liu P, et al. Calycosin modulates inflammation via suppressing TLR4/NF-κB pathway and promotes bone formation to ameliorate glucocorticoid-induced osteonecrosis of the femoral head in rat. Phytother Res, 2021. doi: 10.1002/ptr.7028.
24. Deng Z, Ren Y, Park MS, et al. Damage associated molecular patterns in necrotic femoral head inhibit osteogenesis and promote fibrogenesis of mesenchymal stem cells. Bone, 2022, 154: 116215. doi: 10.1016/j.bone.2021.116215.
25. Adapala NS, Yamaguchi R, Phipps M, et al. Necrotic bone stimulates proinflammatory responses in macrophages through the activation of toll-like receptor 4. Am J Pathol, 2016, 186(11): 2987-2999.
26. Locati M, Curtale G, Mantovani A. Diversity, mechanisms, and significance of macrophage plasticity. Annu Rev Pathol, 2020, 15: 123-147.
27. Jin T, Zhang Y, Sun Y, et al. IL-4 gene polymorphisms and their relation to steroid-induced osteonecrosis of the femoral head in Chinese population. Mol Genet Genomic Med, 2019, 7(3): e563. doi: 10.1002/mgg3.563.
28. von Kaeppler EP, Wang Q, Raghu H, et al. Interleukin 4 promotes anti-inflammatory macrophages that clear cartilage debris and inhibits osteoclast development to protect against osteoarthritis. Clin Immunol, 2021, 229: 108784. doi: 10.1016/j.clim.2021.108784.
29. Tian G, Liu C, Gong Q, et al. Human umbilical cord mesenchymal stem cells improve the necrosis and osteocyte apoptosis in glucocorticoid-induced osteonecrosis of the femoral head model through reducing the macrophage polarization. Int J Stem Cells, 2022, 15(2): 195-202.
30. Gkouveris I, Soundia A, Gouveris P, et al. Macrophage involvement in medication-related osteonecrosis of the jaw (MRONJ): A comprehensive, short review. Cancers (Basel), 2022, 14(2): 330. doi: 10.3390/cancers14020330.
31. Poubelle PE, Chakravarti A, Fernandes MJ, et al. Differential expression of RANK, RANK-L, and osteoprotegerin by synovial fluid neutrophils from patients with rheumatoid arthritis and by healthy human blood neutrophils. Arthritis Res Ther, 2007, 9(2): R25. doi: 10.1186/ar2137.
32. Yang N, Liu Y. The Role of the immune microenvironment in bone regeneration. Int J Med Sci, 2021, 18(16): 3697-3707.
33. Dömer D, Walther T, Möller S, et al. Neutrophil extracellular traps activate proinflammatory functions of human neutrophils. Front Immunol, 2021, 12: 636954. doi: 10.3389/fimmu.2021.636954.
34. Nonokawa M, Shimizu T, Yoshinari M, et al. Association of neutrophil extracellular traps with the development of idiopathic osteonecrosis of the femoral head. Am J Pathol, 2020, 190(11): 2282-2289.
35. Vitkov L, Minnich B, Knopf J, et al. NETs are double-edged swords with the potential to aggravate or resolve periodontal inflammation. Cells, 2020, 9(12): 2614. doi: 10.3390/cells9122614.
36. Collin M, Bigley V. Human dendritic cell subsets: an update. Immunology, 2018, 154(1): 3-20.
37. Elsayed R, Kurago Z, Cutler CW, et al. Role of dendritic cell-mediated immune response in oral homeostasis: A new mechanism of osteonecrosis of the jaw. FASEB J, 2020, 34(2): 2595-2608.
38. Wang B, Dong Y, Tian Z, et al. The role of dendritic cells derived osteoclasts in bone destruction diseases. Genes Dis, 2020, 8(4): 401-411.
39. Dong C. Cytokine regulation and function in T cells. Annu Rev Immunol, 2021, 39: 51-76.
40. Wang X, Chen X, Lu L, et al. Alcoholism and osteoimmunology. Curr Med Chem, 2021, 28(9): 1815-1828.
41. Fischer V, Haffner-Luntzer M. Interaction between bone and immune cells: Implications for postmenopausal osteoporosis. Semin Cell Dev Biol, 2022, 123: 14-21.
42. Ono T, Hayashi M, Sasaki F, et al. RANKL biology: bone metabolism, the immune system, and beyond. Inflamm Regen, 2020, 40: 2. doi: 10.1186/s41232-019-0111-3.
43. Deng Z, Zhang Q, Zhao Z, et al. Crosstalk between immune cells and bone cells or chondrocytes. Int Immunopharmacol, 2021, 101(Pt A): 108179. doi: 10.1016/j.intimp.2021.108179.
44. Alvarez C, Suliman S, Almarhoumi R, et al. Regulatory T cell phenotype and anti-osteoclastogenic function in experimental periodontitis. Sci Rep, 2020, 10(1): 19018. doi: 10.1038/s41598-020-76038-w.
45. Lee DSW, Rojas OL, Gommerman JL. B cell depletion therapies in autoimmune disease: advances and mechanistic insights. Nat Rev Drug Discov, 2021, 20(3): 179-199.
46. Yu R, Zhang J, Zhuo Y, et al. ARG2, MAP4K5 and TSTA3 as diagnostic markers of steroid-induced osteonecrosis of the femoral head and their correlation with immune infiltration. Front Genet, 2021, 12: 691465. doi: 10.3389/fgene.2021.691465.
47. Wang Y, Liu J, Burrows PD, et al. B cell development and maturation. Adv Exp Med Biol, 2020, 1254: 1-22.
48. Yoshimoto M. The ontogeny of murine B-1a cells. Int J Hematol, 2020, 111(5): 622-627.
49. Aziz M, Brenner M, Wang P. Therapeutic potential of B-1a cells in COVID-19. Shock, 2020, 54(5): 586-594.
50. Weitzmann MN. Bone and the immune system. Toxicol Pathol, 2017, 45(7): 911-924.
51. Yasuda H. Discovery of the RANKL/RANK/OPG system. J Bone Miner Metab, 2021, 39(1): 2-11.
52. Han YK, Jin Y, Miao YB, et al. Improved RANKL production by memory B cells: A way for B cells promote alveolar bone destruction during periodontitis. Int Immunopharmacol, 2018, 64: 232-237.

Chinese Journal of Reparative and Reconstructive Surgery

Research progress of immune cells regulating the occurrence and development of osteonecrosis of the femoral head

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