QI Baochuang, PENG Zhongyu, YU Weijie, ZHENG Yuanzhi, DONG Zhuoqian, ZOU Chengsong, ZHANG Xihua, XU Yongqing, CHEN Tao .

Advances in the Pathogenesis of Steroid-Induced Necrosis of the Femoral Head

   ［1］ Cui Quanjun， Jo WL， Koo KH， et al. ARCO consensus on the pathogenesis of non-traumatic osteonecrosis of the femoral head［J］. J Korean Med Sci， 2021， 36（10）： e65.

         ［2］  Han Lizhi， Wang Bo， Wang Ruoyu， et al. The shift in the balance between osteoblastogenesis and adipogenesis of mesenchymal stem cells mediated by glucocorticoid receptor［J］. Stem Cell Res Ther， 2019， 10（1）： 377.

         ［3］  Konarski W， Poboży T， Konarska K， et al. Osteonecrosis related to steroid and alcohol use-an update on pathogenesis［J］. Healthcare （Basel）， 2023， 11（13）： 1846.

         ［4］  Roberti A， Tejedor JR， Díaz-Moreno I， et al. Nicotinamide N-methyltransferase （NNMT） regulates the glucocorticoid signaling pathway during the early phase of adipogenesis［J］. Sci Rep， 2023， 13（1）： 8293.

         ［5］  Chang C， Greenspan A， Gershwin ME. The pathogenesis， diagnosis and clinical manifestations of steroid-induced osteonecrosis［J］. J Autoimmun， 2020， 110：102460.

         ［6］  Chen Yu， Tang Boyu， Jiang Weiqian， et al. miR-486-5p Attenuates steroid-induced adipogenesis and osteonecrosis of the femoral head via TBX2/P21 Axis［J］. Stem Cells， 2023， 41（7）： 711-723.

         ［7］  Xia Chenjie， Xu Huihui， Fang Liang， et al. β-catenin inhibition disrupts the homeostasis of osteogenic/adipogenic differentiation leading to the development of glucocorticoid-induced osteonecrosis of the femoral head［J］. Elife， 2024， 12：RP92469.

         ［8］  Tang Boyu， Chen Yu， Zhao Pei， et al. MiR-601-induced BMSCs senescence accelerates steroid-induced osteonecrosis of the femoral head progression by targeting SIRT1［J］. Cell Mol Life Sci， 2023， 80（9）： 261.

         ［9］  Wu Hongliang， Chen Guocheng， Zhang Guibao， et al. Mechanism of vascular endothelial cell-derived exosomes modified with vascular endothelial growth factor in steroid-induced femoral head necrosis［J］. Biomed Mater， 2023， 18（2）：36794758.

         ［10］ Kerachian MA， Séguin C， Harvey EJ. Glucocorticoids in osteonecrosis of the femoral head： a new understanding of the mechanisms of action［J］. J Steroid Biochem Mol Biol， 2009， 114（3-5）： 121-128.

         ［11］ Zhang Fei， Wei Lei， Wang Lei， et al. FAR591 promotes the pathogenesis and progression of SONFH by regulating Fos expression to mediate the apoptosis of bone microvascular endothelial cells［J］. Bone Res， 2023， 11（1）： 27.

         ［12］ Cao Fang， Qin Kairong， Kang Kai， et al. Ginkgo biloba L. extract prevents steroid-induced necrosis of the femoral head by rescuing apoptosis and dysfunction in vascular endothelial cells via the PI3K/AKT/eNOS pathway［J］. J Ethnopharmacol， 2022， 296：115476.

         ［13］ Sun Kai， Xue Yuman， Zhang Xin， et al. Tanshinone I alleviates steroid-induced osteonecrosis of femoral heads and promotes angiogenesis： in vivo and in vitro studies［J］. J Orthop Surg Res， 2023， 18（1）： 474.

         ［14］ Zhao Xin， Chen Changjun， Luo Yue， et al. Connexin43 overexpression promotes bone regeneration by osteogenesis and angiogenesis in rat glucocorticoid-induced osteonecrosis of the femoral head［J］. Dev Biol， 2023， 496：73-86.

         ［15］ Cao Huijuan， Shi Keda， Long Jing， et al. PDGF-BB prevents destructive repair and promotes reparative osteogenesis of steroid-associated osteonecrosis of the femoral head in rabbits［J］. Bone， 2023， 167：116645.

         ［16］ Yue Ju'an， Yu Huachen， Liu Pei， et al. Preliminary study of icariin indicating prevention of steroid-induced osteonecrosis of femoral head by regulating abnormal expression of miRNA-335 and protecting the functions of bone microvascular endothelial cells in rats［J］. Gene， 2021， 766： 145128.

         ［17］ Jiang Hongyi， Wang Weidan， Mao Yiwen， et al. Morroniside-mediated mitigation of stem cell and endothelial cell dysfunction for the therapy of glucocorticoid-induced osteonecrosis of the femoral head［J］. Int Immunopharmacol， 2024， 127：111421.

         ［18］ Peng Peng， He Wei， Zhang Yixi， et al. CircHIPK3 promotes bone microvascular endothelial cell proliferation， migration and angiogenesis by targeting miR-7 and KLF4/VEGF signaling in steroid-induced osteonecrosis of the femoral head［J］. Adv Clin Exp Med， 2023， 32（1）： 43-55.

         ［19］ Hu Kangyi， Shang Zhengya， Yang Xiaorui， et al. Macrophage polarization and the regulation of bone immunity in bone homeostasis［J］. J Inflamm Res， 2023， 16：3563-3580.

         ［20］ Cheng Yannan， Chen Hui， Duan Ping， et al. Early depletion of M1 macrophages retards the progression of glucocorticoid-associated osteonecrosis of the femoral head［J］. Int Immunopharmacol， 2023， 122：110639.

         ［21］ Jiang Chaolai， Zhou Zubin， Lin Yiwei， et al. Astragaloside IV ameliorates steroid-induced osteonecrosis of the femoral head by repolarizing the phenotype of pro-inflammatory macrophages［J］. Int Immunopharmacol， 2021， 93：107345.

         ［22］ Tian Gang， Liu Chuanjie， Gong Qi， 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［J］. Int J Stem Cells， 2022， 15（2）： 195-202.

         ［23］ Dai Junwei， Tao Jun， Wei Shusheng， et al. The mechanism of NK cell expression of RANKL/RANK/OPG pathway in mouse models of femoral head necrosis［J］. Ann Med Surg （Lond）， 2025， 87（9）： 5494-5502.

         ［24］ Li Xuhuan， Qian Shida， Chen Dan， et al. A new mechanism in steroid-induced osteonecrosis of the femoral head and the protective role of simvastatin［J］. Exp Cell Res， 2025， 446（1）： 114471.

         ［25］ Lin Lishan， Yu Yaling， Liu Kangping， et al. Downregulation of miR-30b-5p facilitates chondrocyte hypertrophy and apoptosis via targeting runx2 in steroid-Induced osteonecrosis of the femoral head［J］. Int J Mol Sci， 2022， 23（19）：11275.

         ［26］ Li Hui， Zhang Yufei， Hao Yangquan， et al. Proanthocyanidins inhibit osteoblast apoptosis via the PI3K/AKT/Bcl-xL pathway in the treatment of steroid-induced osteonecrosis of the femoral head in rats［J］. Nutrients， 2023， 15（8）：1936.

         ［27］ Zhang Shenyao， Dong Kefang， Zeng Xiangjing， et al. Astragalus polysaccharide ameliorates steroid-induced osteonecrosis of the femoral head by regulating miR-200b-3p-mediated Wnt/β-catenin signaling pathway via inhibiting SP1 expression： astragalus polysaccharide regulates SONFH via SP1［J］. BMC Musculoskelet Disord， 2023， 24（1）： 369.

         ［28］ Jia Bin， Jiang Yaping， Yao Yao， et al. Baicalin attenuates dexamethasone-induced apoptosis of bone marrow mesenchymal stem cells by activating the hedgehog signaling pathway［J］. Chin Med J （Engl）， 2023， 136（15）： 1839-1847.

         ［29］ Liang Xuezhen， Luo Di， Chen Yanrong， et al. Identification of potential autophagy-related genes in steroid-induced osteonecrosis of the femoral head via bioinformatics analysis and experimental verification［J］. J Orthop Surg Res， 2022， 17（1）： 86.

         ［30］ Jang Boyong， Guo Shibing， Bai Rui， et al. Methylprednisolone inhibits autophagy of vascular endothelial cells in rat femoral head via PI3K/Akt/mTOR pathway［J］. Orthop Surg， 2022， 14（10）： 2669-2681.

         ［31］ Zhang Yaqi， Jiang Tongmeng， Li Bo， et al. Mst1 inhibition mitigates steroid-induced femoral head osteonecrosis by modulating autophagy in bone microvascular endothelial cells［J］. Biochem Pharmacol， 2025， 239： 117081.

         ［32］ Zheng Kai， Li Wenming， Wang Tianhao， et al. Dopamine D1 receptor contributes to glucocorticoid-associated osteonecrosis of femoral head protection through the ATF3/CHOP axis to inhibit osteoblastic apoptosis［J］. Adv Sci （Weinh）， 2025， 12（33）： e02276.

         ［33］ Wang Tao， Xie Zhihong， Wang Lei， et al. LncAABR07053481 inhibits bone marrow mesenchymal stem cell apoptosis and promotes repair following steroid-induced avascular necrosis［J］. Commun Biol， 2023， 6（1）： 365.

         ［34］ Shan Haojie， Lin Yiwei， Yin Fuli， et al. Effects of astragaloside IV on glucocorticoid-induced avascular necrosis of the femoral head via regulating Akt-related pathways［J］. Cell Prolif， 2023， 56（11）： e13485.

         ［35］ Ma Liang， Feng Xiaobo， Wang Kun， et al. Dexamethasone promotes mesenchymal stem cell apoptosis and inhibits osteogenesis by disrupting mitochondrial dynamics［J］. FEBS Open Bio， 2020， 10（2）： 211-220.

         ［36］ Liu Bo， Gao Feng， Xiu Xiaofei， et al. Denosumab can prevent collapse in patients with early-stage steroid-induced osteonecrosis of the femoral head by inhibiting osteoclasts and autophagy［J］. Orthop Surg， 2023， 15（1）： 256-265.

         ［37］ Meng Kairui， Liu Yicheng， Ruan Lvqiang， et al. Suppression of apoptosis in osteocytes， the potential way of natural medicine in the treatment of osteonecrosis of the femoral head［J］. Biomed Pharmacother， 2023， 162：114403.

         ［38］ Li Jie， Cao Feng， Yin Heliang， et al. Ferroptosis： past， present and future［J］. Cell Death Dis， 2020， 11（2）： 88.

         ［39］ Sun Fei， Zhou Jianlin， Liu Zilin， et al. Dexamethasone induces ferroptosis via P53/SLC7A11/GPX4 pathway in glucocorticoid-induced osteonecrosis of the femoral head［J］. Biochem Biophys Res Commun， 2022， 602：149-155.

         ［40］ Chen Ning， Meng Yuan， Zhan Huixian， et al. Identification and validation of potential ferroptosis-related genes in glucocorticoid-induced osteonecrosis of the femoral head［J］. Medicina （Kaunas）， 2023， 59（2）： 297.

         ［41］ Liu Jian， Han Xueliang， Qu Lianjun， et al. Identification of key ferroptosis-related biomarkers in steroid-induced osteonecrosis of the femoral head based on machine learning［J］. J Orthop Surg Res， 2023， 18（1）： 327.

         ［42］ Li Wenming， Li Wenhao， Zhang Wei， et al. Exogenous melatonin ameliorates steroid-induced osteonecrosis of the femoral head by modulating ferroptosis through GDF15-mediated signaling［J］. Stem Cell Res Ther， 2023， 14（1）： 171.

         ［43］ He Yixiang， Qiao Wanjia， Zhang Kui， et al. Identification and validation of SQLE in steroid-induced osteonecrosis of the femoral head： a bioinformatics and experimental study［J］. J Orthop Surg Res， 2025， 20（1）： 894.

         ［44］ Zuo Rongtai， Cao Bojun， Kong Lingchi， et al. MiR-370-3p regulate TLR4/SLC7A11/GPX4 to alleviate the progression of glucocorticoids-induced osteonecrosis of the femoral head by promoting osteogenesis and suppressing ferroptosis［J］. J Orthop Translat， 2025， 51： 337-358.

         ［45］ Zhou Yingbo， Cai Zhangtao， Zhai Yijia， et al. Necroptosis inhibitors： mechanisms of action and therapeutic potential［J］. Apoptosis， 2024， 29（1-2）： 22-44.

         ［46］ Fan Xiaoyu， Xu Xin， Wu Xinjie， et al. The protective effect of DNA aptamer on osteonecrosis of the femoral head by alleviating TNF-α-mediated necroptosis via RIP1/RIP3/MLKL pathway［J］. J Orthop Translat， 2022， 36：44-51.

         ［47］ Feng Min， Zhang Ruirui， Zhang Mingming， et al. Administration of necrostatin-1 ameliorates glucocorticoid-induced osteonecrosis of the femoral head in rats［J］. J Mol Histol， 2023， 54（3）： 207-216.

         ［48］ Zhou Wanwan， Wang Xiao， Chang Jun， et al. The molecular structure and biological functions of RNA methylation， with special emphasis on the roles of RNA methylation in autoimmune diseases［J］. Crit Rev Clin Lab Sci， 2022， 59（3）： 203-218.

         ［49］ Zhang Man， Zeng Yunping， Peng Rong， et al. N（6）-methyladenosine RNA modification regulates photosynthesis during photodamage in plants［J］. Nat Commun， 2022， 13（1）： 7441.

         ［50］ Yang Chuan， Dong Zicai， Ling Zhiguo， et al. The crucial mechanism and therapeutic implication of RNA methylation in bone pathophysiology［J］. Ageing Res Rev， 2022， 79：101641.

         ［51］ Liang Jianhui， Yi Qian， Liu Yang， et al. Recent advances of m6A methylation in skeletal system disease［J］. J Transl Med， 2024， 22（1）： 153.

         ［52］ Cheng Cheng， Zhang Haoping， Zheng Jia， et al. METTL14 benefits the mesenchymal stem cells in patients with steroid-associated osteonecrosis of the femoral head by regulating the m6A level of PTPN6［J］. Aging （Albany NY）， 2021， 13（24）： 25903-25919.

         ［53］ Gu Yong， Wang Zhengming， Wang Rui， et al. N6-methyladenine regulator-mediated RNA methylation modification patterns in immune microenvironment regulation of osteoarthritis［J］. Front Genet， 2023， 14：1113515.

         ［54］ Sun Menghu， Cao Yuju， Yang Xiaolong， et al. DNA methylation in the OPG/RANK/RANKL pathway is associated with steroid-induced osteonecrosis of the femoral head［J］. BMC Musculoskelet Disord， 2021， 22（1）： 599.

         ［55］ Qin Wentao， Jiang Mingyang， Lu Shenyi， et al. Effects of external environment on promoter methylation of PIK3R5 and related pathway regulation in steroid-induced femoral head necrosis［J］. Environ Res， 2023， 238（Pt 1）： 117116.

         ［56］ Huang Ronglan， Zhan Qinghao， Hu Wenbin， et al. Association of ABCB1 and CYP450 gene polymorphisms and their DNA methylation status with steroid-induced osteonecrosis of the femoral head in the Chinese population［J］. Genet Test Mol Biomarkers， 2020， 24（12）： 789-797.

         ［57］ Lin Tao， Zhang Zheng， Wu Jinhui， et al. A ROS/GAS5/SIRT1 reinforcing feedback promotes oxidative stress-induced adipogenesis in bone marrow-derived mesenchymal stem cells during osteoporosis［J］. Int Immunopharmacol， 2023， 114：109560.

         ［58］ Yang Ning， Sun Houyi， Xue Yi， et al. Inhibition of MAGL activates the Keap1/Nrf2 pathway to attenuate glucocorticoid-induced osteonecrosis of the femoral head［J］. Clin Transl Med， 2021， 11（6）： e447.

         ［59］ Jiang Hongyi， Lin Chihao， Cai Tingwen， et al. Taxifolin-mediated Nrf2 activation ameliorates oxidative stress and apoptosis for the treatment of glucocorticoid-induced osteonecrosis of the femoral head［J］. Phytother Res， 2024， 38（1）： 156-173.

         ［60］ Zhang Xinglong， Pang Ran， Zhang Kai， et al. Apocynin exerts cytoprotective effects on dexamethasone-induced osteoblasts by inhibiting oxidative stress through the Nrf2 signalling pathway［J］. J Cell Mol Med， 2023， 27（23）： 3911-3927.

         ［61］ Peng Peng， He Mincong， Fang Weihua， et al. Plasma 8-OHdG act as a biomarker for steroid-induced osteonecrosis of the femoral head［J］. BMC Musculoskelet Disord， 2023， 24（1）： 808.

         ［62］ Ma Zheru， Sun Jing， Jiang Qi， et al. Identification and analysis of mitochondria-related central genes in steroid-induced osteonecrosis of the femoral head， along with drug prediction［J］. Front Endocrinol （Lausanne）， 2024， 15：1341366.

         ［63］ Shi Wei， Zhang Xinglong， Xu Chunlei， et al. Identification of hub genes and pathways associated with oxidative stress of cartilage in osteonecrosis of femoral head using bioinformatics analysis［J］. Cartilage， 2022， 13（1）： 19476035221074000.

         ［64］ Beytemur O， Dasci MF， Gök Yurttaş A， et al. The protective role of vitamins C and E in steroid-induced femoral head osteonecrosis：an experimental study in rats［J］. Jt Dis Relat Surg， 2024， 35（1）： 72-84.

         ［65］ Gao Yuan， You Yunhao， Zhang Pengfei， et al. Cortistatin prevents glucocorticoid-associated osteonecrosis of the femoral head via the GHSR1a/Akt pathway［J］. Commun Biol， 2024， 7（1）： 132.

         ［66］ Fang Shanhong， He Tianmin， You Mengqiang， et al. Glucocorticoids promote steroid-induced osteonecrosis of the femoral head by down-regulating serum alpha-2-macroglobulin to induce oxidative stress and facilitate SIRT2-mediated BMP2 deacetylation［J］. Free Radic Biol Med， 2024， 213：208-221.

         ［67］ Xi Hongzhong， Chen Hao， Fu Jiahao， et al. Traditional Chinese medicine Youguiyin decoction ameliorate glucocorticoid-induced osteonecrosis in rat by modulating ROS/PHD2/HIF-1α oxidative stress signaling pathway in bone marrow mesenchymal stem cells［J］. Chin Med， 2025， 20（1）： 55.

         ［68］ Chen Kai， Qiu Pengcheng， Yuan Yu， et al. Pseurotin a inhibits osteoclastogenesis and prevents ovariectomized-induced bone loss by suppressing reactive oxygen species［J］. Theranostics， 2019， 9（6）： 1634-1650.

         ［69］ Wang Feng， Min Hongsun， Shan Haojie， et al. IL-34 aggravates steroid-induced osteonecrosis of the femoral head via promoting osteoclast differentiation［J］. Immune Netw， 2022， 22（3）： e25.

         ［70］ Zhang Peng， Xu Huihui， Wang Pinger， et al. Yougui pills exert osteoprotective effects on rabbit steroid-related osteonecrosis of the femoral head by activating β-catenin［J］. Biomed Pharmacother， 2019， 120：109520.

         ［71］ Ozawa Y， Takegami Y， Osawa Y， et al. Anti-sclerostin antibody therapy prevents post-ischemic osteonecrosis bone collapse via interleukin-6 association［J］. Bone， 2024， 181： 117030.

         ［72］ Liu Yuhao， Mo Liang， Lu Hongduo， et al. Dragon blood resin ameliorates steroid-induced osteonecrosis of femoral head through osteoclastic pathways［J］. Front Cell Dev Biol， 2023， 11：1202888.

         ［73］ An Senbo， Hu Huiyu， Li Yusheng， et al. Pyroptosis plays a role in osteoarthritis［J］. Aging Dis， 2020， 11（5）： 1146-1157.

         ［74］ Bergsbaken T， Fink SL， Cookson BT. Pyroptosis： host cell death and inflammation［J］. Nat Rev Microbiol， 2009， 7（2）： 99-109.

         ［75］ Lu Fangfang， Lan Zhixin， Xin Zhaoqi， et al. Emerging insights into molecular mechanisms underlying pyroptosis and functions of inflammasomes in diseases［J］. J Cell Physiol， 2020， 235（4）： 3207-3221.

         ［76］ Paludan SR， Reinert LS， Hornung V. DNA-stimulated cell death： implications for host defence， inflammatory diseases and cancer［J］. Nat Rev Immunol， 2019， 19（3）： 141-153.

         ［77］ Chai Jinlian， Lu Bowen， Du Haitao， et al. Pyroptosis -related potential diagnostic biomarkers in steroid-induced osteonecrosis of the femoral head［J］. BMC Musculoskelet Disord， 2023， 24（1）： 609.

         ［78］ An Feimeng， Zhang Litian， Gao Hongyan， et al. Variants in RETN gene are associated with steroid-induced osteonecrosis of the femoral head risk among Han Chinese people［J］. J Orthop Surg Res， 2020， 15（1）： 96.

         ［79］ Wang Yuan， Wang Yexin， Liang Da， et al. MIR31HG polymorphisms are related to steroid-induced osteonecrosis of femoral head among Chinese Han population［J］. BMC Musculoskelet Disord， 2022， 23（1）： 836.

         ［80］ Tian Cong， Shao Wenhui， Zhou Honghai. Transcriptomic analysis reveals genetic factors regulating early steroid-induced osteonecrosis of the femoral head［J］. Medicine （Baltimore）， 2022， 101（37）： e30625.

         ［81］ Qi Baochuang， Li Chuan， Cai Xingbo， et al. Bioinformatics-based analysis of key genes in steroid-induced osteonecrosis of the femoral head that are associated with copper metabolism［J］. Biomedicines， 2023， 11（3）：873.

         ［82］ Li Zilin， Han Lizhi， Wang Bo， et al. The role of Piezo1 in bone marrow stem cells in response to elevated intraosseous pressure on regulating osteogenesis and angiogenesis of steroid-induced osteonecrosis of the femoral head［J］. J Orthop Translat， 2025， 51： 278-289.

         ［83］ 莫小凤， 杨勇. 住院患者糖皮质激素药物使用情况及合理性分析［J］. 中国药物评价， 2020， 37（4）： 306-309.