PTEN inhibitor VO-OHpic attenuates GC-associated endothelial progenitor cell dysfunction and osteonecrosis of the femoral head via activating Nrf2 signaling and inhibiting mitochondrial apoptosis pathway

Abstract

Background: Glucocorticoid (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. Methods: We 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. Results: The 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.

Exosomal miR-100-5p Inhibits Osteogenesis of BMSCs and Angiogenesis of VECs By Suppressing BMPR2/Smad1/5/9 Signaling Pathway

“…For the difficulty in early diagnosis and its irreversible progress, NONFH result in heavy economic burden 40 . Based on previous studies, the pathogenesis of NONFH can be mainly summarized as follows :(I) impaired angiogenesis of vascular endothelial cells and (II) reduced osteogenic activity and increased adipogenesis of BMSCs [41][42][43][44] . In this study, we found that expressions of osteogenic and angiogenic markers were decreased in necrotic bone tissue of NONFH, accompanied with an augment of adipogenic marker.…”

The role of the Nrf2/Keap1 signaling cascade in mechanobiology and bone health

“…The detrimental effects of oxidative stress come into play when ROS levels are not adequately balanced by antioxidant function and become elevated ( Domazetovic et al, 2017 ; Yao et al, 2020 ). Some behaviors and disease states are characterized by elevated and persistent oxidative stress, including heavy smoking, long-term alcohol abuse, type-2 diabetes mellitus (T2DM), osteoporosis, Alzheimer's and Huntington's disease.…”

“…These foreign substances, known as xenobiotics, contribute to cellular redox reactions which form reactive oxygen species (ROS) ( Pagano, 2002 ). Some ROS, however, are produced naturally – as byproducts of normal metabolic processes ( Yao et al, 2020 ). Although these ROS are oxidants and cellular stressors, they play an essential role in some cellular signaling pathways, and are therefore necessary at low physiological levels ( Yao et al, 2020 ).…”

“…Some ROS, however, are produced naturally – as byproducts of normal metabolic processes ( Yao et al, 2020 ). Although these ROS are oxidants and cellular stressors, they play an essential role in some cellular signaling pathways, and are therefore necessary at low physiological levels ( Yao et al, 2020 ). Complete elimination of ROS would greatly impair functions such as bone marrow homeostasis ( Yen and Hsiao, 2018 ).…”

“…A recent rat study investigating the effects of VO-OHpic, (a powerful inhibitor of PTEN) activates the Nrf2 pathway, and this activation is critical to the protective effect of VO-OHpic. This indicates that PTEN may repress Nrf2 activity ( Yao et al, 2020 ), suggesting that activation of Nrf2 may help to prevent bone loss caused by long term use of GC.…”