Leptin accelerates BMSC transformation into vertebral epiphyseal plate chondrocytes by activating SENP1‐mediated deSUMOylation of SIRT3

Abstract

Bone marrow mesenchymal stem cells (BMSCs) are capable of multidirectional differentiation, and engrafted BMSCs can be used to replace damaged chondrocytes for treatment of intervertebral disc disease. However, chondroblast differentiation of implanted BMSCs is inhibited by the anoxic environment of the articular cavity. Here, we found that leptin enhanced the transformation of BMSCs into chondrocytes under hypoxic conditions. BMSCs isolated from mice were cultured in medium supplemented with leptin under hypoxia. The expression of MFN1/2 and OPA1 were increased only in BMSCs cultured in an anoxic environment. In addition, in hypoxic environments cell energy metabolism relies on glycolysis regulated by leptin, rather than by mitochondrial oxidation. The expression of the de‐SUMOylation protease SENP1 was elevated, leading to SIRT3‐mediated activation of PGC‐1α; these processes were regulated by CREB phosphorylation, and promoted mitochondrial fusion and cell differentiation. The chondrogenic activity of BMSCs isolated from SIRT3‐knockout mice was lower than that of BMSCs isolated from wildtype mice. Implantation of SIRT3‐knockout murine‐derived BMSCs did not significantly improve the articular cartilage layer of the disc. In conclusion, the hypoxic microenvironment promoted BMSC differentiation into chondrocytes, whereas osteoblast differentiation was inhibited. SENP1 activated SIRT3 through the deSUMOylation of mitochondria and eliminated the antagonistic effect of SIRT3 acetylation on phosphorylation. When phosphorylation activity of CREB was increased, phosphorylated CREB is then transferred to the nucleus, affecting PGC‐1α. This promotes mitochondrial fusion and differentiation of BMSCs. Leptin not only maintains chondrogenic differentiation homeostasis of BMSCs, but also provides energy for differentiation of BMSCs under hypoxic conditions through glycolysis.

Effects of radiation mitigating amino acid mixture on mice of different sexes

“…In addition, leptin levels were also increased by MAAM treatment in these mouse sera. Leptin, a hormone produced in adipocytes, plays a crucial role in maintaining a normal body weight and regulating energy expenditure (23)(24)(25). Our current data suggest that, in addition to the previously reported mitigative effects of GI-ARS in male Swiss mice, MAAM may also enhance the survival of male CD2F1 mice following radiation exposure by protecting against radiation-induced hematopoietic system failure.…”

Integrated Network Pharmacology and Experimental Validation Approach to Investigate the Mechanisms of Radix Rehmanniae Praeparata - Angelica Sinensis - Radix Achyranthis Bidentatae in Treating Knee Osteoarthritis

“… 47 According to Sun et al, IL-1β-mediated NADPH oxidase (Nox4) in chondrocyte metabolism might create excessive ROS, leading to matrix metalloproteinase-13 (MMP-13) release and articular cartilage breakdown. 48 Interestingly, treatment with RAR reversed the effects of IL-1β on the increase in ROS and decrease in SOD and GSH levels in chondrocytes. These findings confirmed the indispensability of RAR in the regulation of oxidative damage to articular cartilage.…”

How to enhance the ability of mesenchymal stem cells to alleviate intervertebral disc degeneration

“…Significant progress has been made in the treatment of IDD by MSCs, but due to the harsh environment of the IDs[ 5 ], the therapeutic effect of MSCs is reduced due to the lack of oxygen in the environment[ 61 ]. However, it has been found that the differentiation of MSCs to chondrocytes under hypoxic conditions can be helped by the addition of leptin[ 62 ], which provides energy for cell differentiation through its dependent glycolysis.…”