Effects of osteoblast autophagy on glucocorticoid-induced femoral head necrosis

Zhou, Ming; Liu, Lei; Xu, Yaozeng; Jiang, Jiannong; Liu, Gang; Zhai, Chenjun

doi:10.5606/ehc.2020.73036

Cited by 8 publications

(13 citation statements)

References 31 publications

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“…For instance, Han et al 30 found that autophagy could relieve the functional inhibition and apoptosis-promoting effects on osteoblasts induced by glucocorticoids. Zhou et al 31 suggested that autophagy played a crucial protective role in the pathogenesis of steroid ONFH. The enhancement of autophagy levels could be an important target for the prevention or treatment of ONFH.…”

Section: Protective Mechanism Of Denosumabmentioning

confidence: 99%

Denosumab Can Prevent Collapse in Patients with Early‐Stage Steroid‐Induced Osteonecrosis of the Femoral Head by Inhibiting Osteoclasts and Autophagy

Liu

Gao

Xiu

et al. 2022

Orthopaedic Surgery

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Objective The osteoclastic bone resorption inhibitors might have positive effect in preventing femoral head collapse in patients with osteonecrosis of the femoral head (ONFH). However, as a novel osteoclastic inhibitor, whether denosumab can prevent collapse in steroid‐induced ONFH remains unknown. This study aims to evaluate the treatment effect of denosumab and the potential protective mechanism. Methods This was a retrospective study. A total of 161 patients with steroid‐induced ONFH who underwent denosumab treatment were reviewed, and 209 untreated patients were selected as controls. Their clinical characteristics and radiological exam results were obtained. Patients were treated with 60 mg denosumab every 6 months for 2 years. The primary outcome was the incidence of femoral head collapse at 2 years after the initial diagnosis of ONFH. Secondary outcomes included the Harris hip score, progression of osteosclerosis, increase in necrotic area, bone marrow oedema relief, and bone mineral density increase in the femoral head. The Mann–Whitney U test and chi‐square tests were performed to identify the differences between the continuous and categorical variables, respectively. A multivariate logistic regression model was built to identify the factors associated with the treatment effect of denosumab. Results The incidence of femoral head collapse was 42.24% (68/161) in the denosumab group and 54.07% (113/209) in the control group (χ2 = 5.094, p = 0.024; relative risk = 0.787, 95% CI = 0.627–0.973). The excellent‐good rates of the Harris hip score were 63.98% (103/161) in the denosumab group and 44.98% (94/209) in the control group (χ2 = 13.186, p < 0.001). The incidence of osteosclerosis progression in the denosumab group was 55.28% (89/161), which was significantly higher than that in the control group (43.54%, 91/209, χ2 = 5.016, p = 0.025). Meanwhile, a significant increase in bone mineral density was identified in 29.19% (47/161) and 7.18% (15/209) of patients in the denosumab and control groups, respectively (χ2 = 31.600, p < 0.001). The osteoclastic cytoplasm expression of LC3‐II was more positive in the control group than in the denosumab group (immunohistochemistry scoring: 3.58 ± 2.27 vs 6.33 ± 2.64, Z = −2.684, p = 0.007). A total of three independent factors were considered to be associated with the positive treatment effect of denosumab, the time of first denosumab administration (OR = 2.010, 95% CI = 1.272–3.177), osteosclerosis (OR = 1.583, 95% CI = 1.024–2.445), and the necrotic area before denosumab administration (medium necrotic area: OR = 2.084, 95% CI = 1.245–3.487; large necrotic area: OR = 2.211, 95% CI = 1.255–3.893). Conclusions The current study demonstrated that denosumab had a positive effect on preventing femoral head collapse in patients with steroid ONFH. This effect might be closely associated with the inhibition of osteoclasts and their autophagy.

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Section: Protective Mechanism Of Denosumabmentioning

confidence: 99%

Denosumab Can Prevent Collapse in Patients with Early‐Stage Steroid‐Induced Osteonecrosis of the Femoral Head by Inhibiting Osteoclasts and Autophagy

Liu

Gao

Xiu

et al. 2022

Orthopaedic Surgery

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“…Calibrations for bone mineral density (BMD) were first applied to dataset. All BMDs were analyzed using calcium densities 0.25 g/mm 3 and 0.75 g/mm 3 CaHA calibration bar (phantom).…”

Section: Radiological Examinationmentioning

confidence: 99%

“…Using the ROI created in the femoral head, BMD in g/cm 3 , bone volume/total volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), porosity, trabecular distance (Tr.Sp. ), trabecular separation (Tr.Sep), trabecular bone model factor (Tb.Pf.…”

Section: Radiological Examinationmentioning

confidence: 99%

“…The decrease of autophagy level induced by dexamethasone may be one of the causes of steroid-induced ON. [ 3 ] Vascular endothelial dysfunction, which is capable of increasing hypercoagulation, has also played a role in the pathophysiology of steroid-induced ON. Recent studies have reported that in vivo oxidative stress plays an essential role in the pathogenesis of steroidinduced ON.…”

Section: Introductionmentioning

confidence: 99%

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The effects of thymoquinone on steroid-induced femoral head osteonecrosis: An experimental study in rats

Daşcı

Saraç²,

Yurttaş³

et al. 2022

Jt Dis Relat Surg

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Steroid-induced osteonecrosis (ON) of the femoral head represents one of the most significant complications of long-term high-dose steroid use. [1] Steroids are commonly used in the treatment of chronic autoimmune diseases such as systemic lupus erythematosus, nephrotic syndrome, asthma, after the organ transplantation, and in the patients hospitalized due to novel coronavirus disease-2019 (COVID-19). [2] The early diagnosis of ON of the femoral head (ONFH) is critical, since it mainly influences the young and middle-aged population, and progression of the disease to collapse of the femoral head occurs in most patients, if untreated.Although it has been argued that steroid-induced ON develops due to an ischemia in the bone, Objectives: In this study, we aimed to evaluate the antioxidant, antiapoptotic, osteoblastic and hypolipidemic effects of thymoquinone (TQ) treatment on the steroid-induced osteonecrosis of femoral head (ONFH) model in rats. Materials and methods:A total of 24 rats were randomly divided into four groups: the control group administered saline; the TQ group administered 10 mg/kg/day TQ orally; lipopolysaccharide/ methylprednisolone (LPS/MPS) group administered 20 µg/kg intraperitoneally LPS and 40 mg/kg intramuscularly MPS to establish ONFH model; and the LPS/MPS+TQ group administered both LPS/MPS and, then, TQ once daily for four weeks. All rats were sacrificed after intracardiac blood collection and their right femurs were removed.Results: Micro-computed tomography showed a higher bone mineral density and lower porosity, Tr.Sp and Tr.Sep data were detected in the LPS/MPS+TQ group. In histopathology, osteonecrosis increased significantly in the LPS/MPS group and osteonecrosis decreased in the LPS/MPS+TQ group compared to the LPS/MPS group (p=0.0077). Histomorphometric examination revealed that the percentage of BV/TV in the LPS/MPS group was significantly lower compared to control and other groups (p<0.01 and p<0.05, respectively), while it reached normal rates in the LPS/MPS+TQ group. Immunohistochemically, antioxidant, anti-apoptotic, and angiogenesis indicators , malondialdehyde [MDA], B-cell lymphoma [Bcl-2], caspase-3, vascular endothelial growth factor [VEGF]) were significantly improved in tissue and serum with TQ. Furthermore, TQ significantly reduced low-and high-density lipoprotein cholesterol ratio and carboxy-terminal type 1 collagen crosslink (CTX) in serum. Conclusion:Vascular and hematopoietic cell damages that occur due to steroid-induced deoxyribonucleic acid (DNA) oxidative and lipid peroxidative damages in an ONFH model can be successfully ameliorated by TQ administration. This antioxidant and antiapoptotic effects of TQ may be a promising treatment option for early stage of osteonecrosis.

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“…5,6 Recent evidence indicates that autophagy is involved in the regulation of steroid-induced osteoblast apoptosis, which has opened a new avenue of SONFH therapy. 7,8 Autophagy is a complex biological process that involves degrading dysfunctional cellular components and clearing damaged proteins through lysosomal pathways, providing nutrient recycling and generating energy; it is an important process in cell growth, function and homeostasis maintenance. 9,10 Research over the past 10 years has led to the idea that autophagy can help maintain cell homeostasis and normal function in the presence of external insults.…”

Section: Introductionmentioning

confidence: 99%

Aucubin prevents steroid‐induced osteoblast apoptosis by enhancing autophagy via AMPK activation

Chen

Jin

Zhang

et al. 2021

J Cellular Molecular Medi

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Steroid-induced osteoblast apoptosis is a crucial pathological process in steroidinduced osteonecrosis of the femoral head (SONFH). Autophagy can resist apoptosis and AMPK plays an important role in autophagy regulation. Aucubin from the small tree Eucommia ulmoides Oliv., which has a long history of use in orthopaedics and traumatology in Asian medicine, can promote bone formation, but whether it can slow or prevent steroid-osteoblast apoptosis is unclear. Therefore, we investigated the pathogenesis of SONFH and how the osteoblast responds to aucubin under the dexamethasone stimulation. In human femoral head osteonecrosis specimens, we found that the autophage and apoptosis level were increased, and the AMPK signalling was crucial to autophagy. We observed that aucubin could prevent dexamethasone-induced apoptosis in osteoblasts by enhancing the level of autophagy. Further, we confirmed that the regulatory effect of aucubin on autophagy and apoptosis was achieved by activating AMPK signalling. We have demonstrated a mechanism of disease progression and shown that aucubin could enhance autophagy through AMPK signalling to prevent osteoblast apoptosis. These findings provide a basis for the further investigation of the potential therapeutic role of aucubin in the SONFH.

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Effects of osteoblast autophagy on glucocorticoid-induced femoral head necrosis

Cited by 8 publications

References 31 publications

Denosumab Can Prevent Collapse in Patients with Early‐Stage Steroid‐Induced Osteonecrosis of the Femoral Head by Inhibiting Osteoclasts and Autophagy

Denosumab Can Prevent Collapse in Patients with Early‐Stage Steroid‐Induced Osteonecrosis of the Femoral Head by Inhibiting Osteoclasts and Autophagy

The effects of thymoquinone on steroid-induced femoral head osteonecrosis: An experimental study in rats

Aucubin prevents steroid‐induced osteoblast apoptosis by enhancing autophagy via AMPK activation

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