Abstract
BackgroundGlucocorticoid (GC)-associated osteonecrosis of the femoral head (ONFH) is the most common in non-traumatic ONFH. Despite a strong relationship between GC and ONFH, the detailed mechanisms have remained elusive. Recent studies have shown that GC could directly injure the blood vessels and reduce blood supply in the femoral head. Endothelial progenitor cells (EPCs), which were inhibited quantitatively and functionally during ONFH, play an important role in maintaining the normal structure and function of vascular endothelium. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene that promotes cell apoptosis, and its expression was found to be elevated in GC-associated ONFH patients. However, whether direct inhibition of PTEN attenuates GC-associated apoptosis and dysfunction of the EPCs remains largely unknown.MethodsWe investigated the effect of, VO-OHpic, a potent inhibitor of PTEN, in attenuating GC-associated apoptosis and dysfunction of EPCs and the molecular mechanism. SD rats were used to study the effect of VO-OHpic on angiogenesis and osteonecrosis in vivo.ResultsThe results revealed that methylprednisolone (MPS) obviously inhibit angiogenesis of EPCs by inducing apoptosis, destroying the normal mitochondrial structure, and disrupting function of mitochondria. VO-OHpic treatment is able to reverse the harmful effects by inhibiting the mitochondrial apoptosis pathway and activating the NF-E2-related factor 2 (Nrf2) signaling. Si-Nrf2 transfection significantly reduced the protective effects of VO-OHpic on EPCs. Our in vivo studies also showed that intraperitoneal injection of VO-OHpic obviously attenuates the osteonecrosis of the femoral head induced by MPS and potently increases the blood supply in the femoral head.ConclusionTaken together, the data suggests that inhibition of PTEN with VO-OHpic attenuates apoptosis and promotes angiogenesis of EPCs in vitro via activating Nrf2 signaling pathway and inhibiting the mitochondrial apoptosis pathway. Moreover, VO-OHpic also mitigates GC-associated ONFH and potentiates angiogenesis in the femoral head.
Highlights
Glucocorticoid (GC)-associated osteonecrosis of the femoral head (ONFH) is the most common in non-traumatic Osteonecrosis of the femoral head (ONFH)
Taken together, the data suggests that inhibition of Phosphatase and tensin homolog (PTEN) with VO-OHpic attenuates apoptosis and promotes angiogenesis of Endothelial progenitor cells (EPCs) in vitro via activating NF-E2-related factor 2 (Nrf2) signaling pathway and inhibiting the mitochondrial apoptosis pathway
We aimed to investigate three problems: (1) whether GC could induce mitochondrialmediated apoptosis and inhibit angiogenesis of EPCs, (2) whether inhibition of PTEN with VO-OHpic could ameliorate the detrimental effects of GC via activating Nrf2 signaling pathway and inhibiting the mitochondrial apoptosis pathway, and (3) whether intraperitoneal injection of VO-OHpic could promote angiogenesis and inhibit osteonecrosis in GC associated ONFH in rats
Summary
Glucocorticoid (GC)-associated osteonecrosis of the femoral head (ONFH) is the most common in non-traumatic ONFH. Endothelial progenitor cells (EPCs), which were inhibited quantitatively and functionally during ONFH, play an important role in maintaining the normal structure and function of vascular endothelium. Researchers proposed several mechanisms for the development of ONFH Among those hypotheses, vascular hypothesis seems to be the most compelling one. Vascular hypothesis seems to be the most compelling one This hypothesis presumes that damaged vessels and decreased local blood flow in the femoral head plays a pivotal role in the pathogenesis of ONFH [3, 4]. GC could decrease the number of blood vessels, reduce blood supply in the femoral head, and cause osteonecrosis [5]. Several studies demonstrated that in patients with GCassociated ONFH, the number and function of EPCs in the blood are impaired [6, 7]
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