Skip to main content

Advertisement

SpringerLink
Log in

The role of autophagy in steroid necrosis of the femoral head: a comprehensive research review

  • Review Article
  • Published:
International Orthopaedics Aims and scope Submit manuscript

Abstract

Steroid-induced osteonecrosis of the femoral head (ONFH) has the incidence of 9–40% in patients receiving long-term treatment and is mainly involved in the middle and young people. It is mostly bilateral, with a wide range of necrosis and high disability rate, which brings disaster for patients and families. The experimental study shows that autophagy participates in the pathological process of steroid ONFH and is closely related to apoptosis, and the interaction between autophagy and bone cells is related to the dose of hormones. Moreover, autophagy also affects the interaction between osteoblasts and osteoclasts in ONFH. In the present review, we have discussed the role of autophagy in the pathological process of the steroid-induced ONFH.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Mankin HJ (1992) Nontraumatic necrosis of bone (osteonecrosis). N Engl J Med 326:1473–1479

    Article  PubMed  CAS  Google Scholar 

  2. Drescher W, Schlieper G, Floege J, Eitner F (2011a) Steroid-related osteonecrosis—update. Nephrol Dial Transplant 26:2728–2731

    Article  PubMed  CAS  Google Scholar 

  3. McAvoy S, Baker KS, Mulrooney D, Blaes A, Arora M, Burns LJ, Majhail NS (2010) Corticosteroid dose as a risk factor for avascular necrosis of the bone after hematopoietic cell transplantation. Biol Blood Marrow Transplant 16:1231–1236

    Article  PubMed  CAS  Google Scholar 

  4. Yamamoto T, Schneider R, Iwamoto Y, Bullough PG (2006) Rapid destruction of the femoral head after a single intraarticular injection of corticosteroid into the hip joint. J Rheumatol 33:1701–1704

    PubMed  Google Scholar 

  5. Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC (1998a) Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest 102:274–282

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. O’Brien CA, Jia D, Plotkin LI, Bellido T, Powers CC, Stewart SA, Manolagas SC, Weinstein RS (2004a) Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology 145:1835–1841

    Article  PubMed  CAS  Google Scholar 

  7. O’Brien CA, Jia D, Plotkin LI, Bellido T, Powers CC, Stewart SA, Manolagas SC, Weinstein RS (2004b) Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology 145:1835–1841

    Article  PubMed  CAS  Google Scholar 

  8. Kerachian MA, Harvey EJ, Cournoyer D, Chow TY, Nahal A, Seguin C (2011) A rat model of early stage osteonecrosis induced by glucocorticoids. J Orthop Surg Res 6:62

    Article  PubMed  PubMed Central  Google Scholar 

  9. Weinstein RS, Wan C, Liu Q, Wang Y, Almeida M, Brien CAO, Thostenson J, Roberson PK, Boskey AL, Clemens TL, Manolagas SC (2010) Endogenous glucocorticoids decrease skeletal angiogenesis, vascularity, hydration, and strength in aged mice. Aging Cell 9:147–161

    Article  PubMed  CAS  Google Scholar 

  10. Drescher W, Schlieper G, Floege J, Eitner F (2011b) Steroid-related osteonecrosis—an update. Nephrol Dial Transplant 26:2728–2731

    Article  PubMed  CAS  Google Scholar 

  11. Weinstein RS, Nicholas RW, Manolagas SC (2000) Apoptosis of osteocytes in glucocorticoid-induced osteonecrosis of the hip. J Clin Endocrinol Metab 85:2907–2912

    PubMed  CAS  Google Scholar 

  12. Kabata T, Kubo T, Matsumoto T, Nishino M, Tomita K, Katsuda S, Horii T, Uto N, Kitajima I (2000) Apoptotic cell death in steroid induced osteonecrosis: an experimental study in rabbits. J Rheumatol 27:2166–2171

    PubMed  CAS  Google Scholar 

  13. Youm YS, Lee SY, Lee SH (2010a) Apoptosis in the osteonecrosis of the femoral head. Clin Orthop Surg 2:250–255

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ko JY, Wang FS, Wang CJ, Wong T, Chou WY, Tseng SL (2010) Increased Dickkopf-1 expression accelerates bone cell apoptosis in femoral head osteonecrosis. Bone 46:584–591

    Article  PubMed  CAS  Google Scholar 

  15. Mizushima N (2009) Physiological functions of autophagy. Curr Top Microbiol Immunol 335:71–84

    PubMed  CAS  Google Scholar 

  16. Tsujimoto Y, Shimizu S (2005) Another way to die: autophagic programmed cell death. Cell Death Differ 12(Suppl 2):1528–1534

    Article  PubMed  CAS  Google Scholar 

  17. Scott RC, Juhasz G, Neufeld TP (2007) Direct induction of autophagy by Atg1 inhibits cell growth and induces apoptotic. Cell death. Curr Biol 17:1–11

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Funderburk SF, Wang QJ, Yue Z (2010) The Beclin 1-VPS34 complex—at the crossroads of autophagy and beyond. Trends Cell Biol 20:355–362

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Zhong Y, QJ Wang X, Li YY, Backer JM, Chait BT, Heintz N, Yue Z (2009) Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat Cell Biol 11:468–476

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Pattingre S, A Tassa XQ, Garuti R, Liang XH, Mizushima N, Packer M, Schneider MD, Levine B (2005a) Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122:927–939

    Article  PubMed  CAS  Google Scholar 

  21. Kaur J, Debnath J (2015) Autophagy at the crossroads of catabolism and anabolism. Nat Rev Mol Cell Biol 16:461–472

    Article  PubMed  CAS  Google Scholar 

  22. Liang C, Lee JS, Inn KS, Gack MU, and Li Q (2008) Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nat Cell Biol 10(7):776–787

  23. Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J, Kundu M, Kim DH (2009) ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 20:1992–2003

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Tanida I (2011) Autophagosome formation and molecular mechanism of autophagy. Antioxid Redox Signal 14:2201–2214

    Article  PubMed  CAS  Google Scholar 

  25. Jin S, White E (2007) Role of autophagy in cancer: management of metabolic stress. Autophagy 3:28–31

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Crighton D, Wilkinson S, Ryan KM (2007) DRAM links autophagy to p53 and programmed cell death. Autophagy 3:72–74

    Article  PubMed  CAS  Google Scholar 

  27. O'Prey J, Skommer J, Wilkinson S, Ryan KM (2009) Analysis of DRAM-related proteins reveals evolutionarily conserved and divergent roles in the control of autophagy. Cell Cycle 8:2260–2265

    Article  PubMed  CAS  Google Scholar 

  28. Orth P, Anagnostakos K (2013) Coagulation abnormalities in osteonecrosis and bone marrow edema syndrome. Orthopedics 36:290–300

    Article  PubMed  Google Scholar 

  29. Kerachian MA, EJ Harvey DC, Chow TY, Seguin C (2006) Avascular necrosis of the femoral head: vascular hypotheses. Endothelium 13:237–244

    Article  PubMed  Google Scholar 

  30. Yang S, Zhang L (2004) Glucocorticoids and vascular reactivity. Curr Vasc Pharmacol 2:1–12

    Article  PubMed  Google Scholar 

  31. Drescher W, Li H, Lundgaard A, Bunger C, Hansen ES (2006) Endothelin-1-induced femoral head epiphyseal artery constriction is enhanced by long-term corticosteroid treatment. J Bone Joint Surg Am 88(Suppl 3):173–179

    PubMed  Google Scholar 

  32. Kerachian MA, Seguin C, Harvey EJ (2009) Glucocorticoids in osteonecrosis of the femoral head: a new understanding of the mechanisms of action. J Steroid Biochem Mol Biol 114:121–128

    Article  PubMed  CAS  Google Scholar 

  33. Lancerotto L, Orgill DP (2014) Mechanoregulation of angiogenesis in wound healing. Adv Wound Care (New Rochelle) 3:626–634

    Article  Google Scholar 

  34. Domigan CK, Warren CM, Antanesian V, Happel K, Ziyad S, Lee S, Krall A, Duan L, Torres-Collado AX, Castellani LW, Elashoff D, Christofk HR, van der Bliek AM, Potente M, Iruela-Arispe ML (2015) Autocrine VEGF maintains endothelial survival through regulation of metabolism and autophagy. J Cell Sci 128:2236–2248

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Liang X, Ding Y, Zhang Y, Chai YH, He J, Chiu SM, Gao F, Tse HF, Lian Q (2015) Activation of NRG1-ERBB4 signaling potentiates mesenchymal stem cell-mediated myocardial repairs following myocardial infarction. Cell Death Dis 6:e1765

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Zhang Y, Liao S, Yang M, Liang X, Poon MW, Wong CY, Wang J, Zhou Z, Cheong SK, Lee CN, Tse HF, Lian Q (2012) Improved cell survival and paracrine capacity of human embryonic stem cell-derived mesenchymal stem cells promote therapeutic potential for pulmonary arterial hypertension. Cell Transplant 21:2225–2239

    Article  PubMed  Google Scholar 

  37. Zhang Z, Yang M, Wang Y, Wang L, Jin Z, Ding L, Zhang L, Zhang L, Jiang W, Gao G, J Yang BL, Cao F, Hu T (2016) Autophagy regulates the apoptosis of bone marrow-derived mesenchymal stem cells under hypoxic condition via AMP-activated protein kinase/mammalian target of rapamycin pathway. Cell Biol Int 40:671–685

    Article  PubMed  CAS  Google Scholar 

  38. An Y, WJ Liu P, Xue YM, Zhang LQ, Zhu B, Qi M, Li LY, Zhang YJ, Wang QT, Jin Y (2018) Autophagy promotes MSC-mediated vascularization in cutaneous wound healing via regulation of VEGF secretion. Cell Death Dis 9:58

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Weinstein RS (2001) Glucocorticoid-induced osteoporosis. Rev Endocr Metab Disord 2:65–73

    Article  PubMed  CAS  Google Scholar 

  40. DeSelm CJ, Miller BC, Zou W, Beatty WL, van Meel E, Takahata Y, Klumperman J, Tooze SA, Teitelbaum SL, Virgin HW (2011a) Autophagy proteins regulate the secretory component of osteoclastic bone resorption. Dev Cell 21:966–974

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Hara T, Takamura A, Kishi C, Iemura S, Natsume T, Guan JL, Mizushima N (2008) FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells. J Cell Biol 181:497–510

    Article  PubMed  PubMed Central  Google Scholar 

  42. Liu F, Fang F, Yuan H, Yang D, Chen Y, Williams L, Goldstein SA, Krebsbach PH, Guan JL (2013) Suppression of autophagy by FIP200 deletion leads to osteopenia in mice through the inhibition of osteoblast terminal differentiation. J Bone Miner Res 28:2414–2430

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Stenbeck G (2002) Formation and function of the ruffled border in osteoclasts. Semin Cell Dev Biol 13:285–292

    Article  PubMed  CAS  Google Scholar 

  44. Sanjuan MA, Dillon CP, Tait SW, Moshiach S, Dorsey F, Connell S, Komatsu M, Tanaka K, Cleveland JL, Withoff S, Green DR (2007) Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 450:1253–1257

    Article  PubMed  CAS  Google Scholar 

  45. Lee HK, Mattei LM, Steinberg BE, Alberts P, Lee YH, Chervonsky A, Mizushima N, Grinstein S, Iwasaki A (2010) In vivo requirement for Atg5 in antigen presentation by dendritic cells. Immunity 32:227–239

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. DeSelm CJ, Miller BC, Zou W, Beatty WL, van Meel E, Takahata Y, Klumperman J, Tooze SA, Teitelbaum SL, Virgin HW (2011b) Autophagy proteins regulate the secretory component of osteoclastic bone resorption. Dev Cell 21:966–974

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Canalis E, Bilezikian JP, Angeli A, Giustina A (2004) Perspectives on glucocorticoid-induced osteoporosis. Bone 34:593–598

    Article  PubMed  CAS  Google Scholar 

  48. Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC (1998b) Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest 102:274–282

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Nollet M, Santucci-Darmanin S, Breuil V, Al-Sahlanee R, Cros C, Topi M, Momier D, Samson M, Pagnotta S, Cailleteau L, Battaglia S, Farlay D, Dacquin R, Barois N, Jurdic P, Boivin G, Heymann D, F Lafont SSL, Dempster DW, Carle GF, Pierrefite-Carle V (2014) Autophagy in osteoblasts is involved in mineralization and bone homeostasis. Autophagy 10:1965–1977

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Jia D, O'Brien CA, Stewart SA, Manolagas SC, Weinstein RS (2006) Glucocorticoids act directly on osteoclasts to increase their life span and reduce bone density. Endocrinology 147:5592–5599

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Cheng X, Zhu L, J Zhang JY, Liu S, Lv F, Lin Y, Liu G, Peng B (2017) Anti-osteoclastogenesis of mineral trioxide aggregate through inhibition of the autophagic pathway. J Endod 43:766–773

    Article  PubMed  Google Scholar 

  52. Xia X, Kar R, Gluhak-Heinrich J, Yao W, Lane NE, Bonewald LF, Biswas SK, Lo WK, Jiang JX (2010) Glucocorticoid-induced autophagy in osteocytes. J Bone Miner Res 25:2479–2488

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Youm YS, Lee SY, Lee SH (2010b) Apoptosis in the osteonecrosis of the femoral head. Clin Orthop Surg 2:250–255

    Article  PubMed  PubMed Central  Google Scholar 

  54. Boya P, Cohen I, Zamzami N, Vieira HL, Kroemer G (2002) Endoplasmic reticulum stress-induced cell death requires mitochondrial membrane permeabilization. Cell Death Differ 9:465–467

    Article  PubMed  CAS  Google Scholar 

  55. Green DR, Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science 305:626–629

    Article  PubMed  CAS  Google Scholar 

  56. Zong WX, Li C, Hatzivassiliou G, T Lindsten QCY, Yuan J, Thompson CB (2003) Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis. J Cell Biol 162:59–69

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Jia J, Yao W, Guan M, Dai W, Shahnazari M, Kar R, Bonewald L, Jiang JX, Lane NE (2011) Glucocorticoid dose determines osteocyte cell fate. FASEB J 25:3366–3376

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, Packer M, Schneider MD, and Levine B (2005b) Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122:927–939

  59. Erlich S, Mizrachy L, Segev O, Lindenboim L, Zmira O, Adi-Harel S, Hirsch JA, Stein R, Pinkas-Kramarski R (2007) Differential interactions between Beclin 1 and Bcl-2 family members. Autophagy 3:561–568

    Article  PubMed  CAS  Google Scholar 

  60. Han Y, Zhang L, Xing Y, Zhang L, Chen X, Tang P, Chen Z (2018) Autophagy relieves the function inhibition and apoptosis promoting effects on osteoblast induced by glucocorticoid. Int J Mol Med 41:800–808

    PubMed  Google Scholar 

  61. Zhu L, Chen J, Zhang J, Guo C, Fan W, Wang YM, Yan Z (2017) Parathyroid hormone (PTH) induces autophagy to protect osteocyte cell survival from dexamethasone damage. Med Sci Monit 23:4034–4040

    Article  PubMed  PubMed Central  Google Scholar 

  62. Yang YH, Chen K, Li B, Chen JW, Zheng XF, Wang YR, Jiang SD, Jiang LS (2013) Estradiol inhibits osteoblast apoptosis via promotion of autophagy through the ER-ERK-mTOR pathway. Apoptosis 18:1363–1375

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

This study was supported by the Beijing Natural Science Foundation (7174346), The Capital’s Funds for Health Improvement and Research (CFH2018-4-40611), and National Natural Science Foundation of China (81372013, 81672236).

Author information

Authors and Affiliations

  1. Department of Orthopedic Surgery, China-Japan Friendship Institute of Clinical Medicine, Peking Union Medical College, Beijing, 100029, China

    Pan Luo, Fuqiang Gao & Wei Sun

  2. Centre for Osteonecrosis and Joint-Preserving & Reconstruction, Department of Orthopedic Surgery, Beijing Key Laboratory of Arthritic and Rheumatic Diseases, China-Japan Friendship Hospital, Peking Union Medical College, National Health and Family Planning Commission of the People’s Republic of China, Beijing, 100029, China

    Fuqiang Gao, Wei Sun & Zirong Li

  3. Department of Orthopedic Surgery, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, 100029, China

    Fuqiang Gao, Jun Han & Wei Sun

Authors
  1. Pan Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fuqiang Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jun Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zirong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Fuqiang Gao or Wei Sun.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Pan Luo and Fuqiang Gao are joint first authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Luo, P., Gao, F., Han, J. et al. The role of autophagy in steroid necrosis of the femoral head: a comprehensive research review. International Orthopaedics (SICOT) 42, 1747–1753 (2018). https://doi.org/10.1007/s00264-018-3994-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00264-018-3994-8

Keywords

Search

Navigation