P53 and Parkin co-regulate mitophagy in bone marrow mesenchymal stem cells to promote the repair of early steroid-induced osteonecrosis of the femoral head

Abstract

Survival and stemness of bone marrow mesenchymal stem cells (BMSCs) in osteonecrotic areas are especially important in the treatment of early steroid-induced osteonecrosis of the femoral head (ONFH). We had previously used BMSCs to repair early steroid-induced ONFH, but the transplanted BMSCs underwent a great deal of stressinduced apoptosis and aging in the oxidative-stress (OS) microenvironment of the femoral-head necrotic area, which limited their efficacy. Our subsequent studies have shown that under OS, massive accumulation of damaged mitochondria in cells is an important factor leading to stress-induced apoptosis and senescence of BMSCs. The main reason for this accumulation is that OS leads to upregulation of protein 53 (P53), which inhibits mitochondrial translocation of Parkin and activation of Parkin's E3 ubiquitin ligase, which decreases the level of mitophagy and leads to failure of cells to effectively remove damaged mitochondria. However, P53 downregulation can effectively reverse this process. Therefore, we upregulated Parkin and downregulated P53 in BMSCs. We found that this significantly enhanced mitophagy in BMSCs, decreased the accumulation of damaged mitochondria in cells, effectively resisted stress-induced BMSCs apoptosis and senescence, and improved the effect of BMSCs transplantation on early steroidinduced ONFH.

Autophagic Organelles in DNA Damage Response

“…Unlike ATM and RNF8, p53 binds to the RING0 region of Parkin, which interferes with the mitophagy process involved in Parkin, and affects mitochondria quality control, biosynthesis, kinetic regulation, and cellular redox homeostasis (Jung et al, 2017;Korolchuk et al, 2017). These results confirmed that mitophagy was increased by the downregulation of p53 in both in vivo and in vitro experiments using bone marrow mesenchymal stem cells (Zhang et al, 2020).…”

microRNA‐148a‐3p in extracellular vesicles derived from bone marrow mesenchymal stem cells suppresses SMURF1 to prevent osteonecrosis of femoral head

“…25 Moreover, BMSCs can be used to treat ONFH in the region of osteonecrosis. 26 Notably, the primary BMSCs are capable of elevating the cell viability and suppressing the cell apoptosis in the primary osteoblasts. 27 Additionally, EVs were found to promote the proliferation and differentiation in ONFH.…”

“…There are many potential capacities in BMSCs such as the promotion of osteogenesis 25 . Moreover, BMSCs can be used to treat ONFH in the region of osteonecrosis 26 . Notably, the primary BMSCs are capable of elevating the cell viability and suppressing the cell apoptosis in the primary osteoblasts 27 .…”

Vitamin K2 Can Rescue the Dexamethasone-Induced Downregulation of Osteoblast Autophagy and Mitophagy Thereby Restoring Osteoblast Function In Vitro and In Vivo

“…The linkage of p62 to ubiquitin on the mitochondria and LC3-II (the lipidated form of LC3) on autophagosomes provides a physical attachment point for mitophagy (Geisler et al, 2010;Palikaras et al, 2018), and disruption of either PINK1 or Parkin leads to the impaired mitophagy (Han et al, 2015;Lazarou et al, 2015). Interestingly, impaired mitophagic function have been reported to negatively impact osteoblast differentiation and mineralization function in vitro (Shen et al, 2018b;Jing et al, 2020) and the restoration of mitophagy helps alleviate steriod-induced bone loss in vivo (Zhang et al, 2020). Despite these encouraging reports, the precise role of autophagy and mitophagy in osteoblastic differentiation and function has not been thoroughly explored.…”