PGC-1α in osteoarthritic chondrocytes: From mechanism to target of action

Abstract

Osteoarthritis (OA) is one of the most common degenerative joint diseases, often involving the entire joint. The degeneration of articular cartilage is an important feature of OA, and there is growing evidence that the mitochondrial biogenesis master regulator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) exert a chondroprotective effect. PGC-1α delays the development and progression of OA by affecting mitochondrial biogenesis, oxidative stress, mitophagy and mitochondrial DNA (mtDNA) replication in chondrocytes. In addition, PGC-1α can regulate the metabolic abnormalities of OA chondrocytes and inhibit chondrocyte apoptosis. In this paper, we review the regulatory mechanisms of PGC-1α and its effects on OA chondrocytes, and introduce potential drugs and novel nanohybrid for the treatment of OA which act by affecting the activity of PGC-1α. This information will help to further elucidate the pathogenesis of OA and provide new ideas for the development of therapeutic strategies for OA.

Keywords: PGC- 1α; apoptosis; chondrocyte; metabolism; mitochondria; osteoarthritis.

FIGURE 1

Regulatory mechanisms and molecules of PGC-1α in chondrocytes. AMPK can directly phosphorylate and activate PGC-1α, and can also activate SIRT1 by regulating NAD⁺/NADH, thereby acetylating and activating PGC-1α; PGC-1α can further promote the production of NRF1, NRF2 and TFAM; REDD1 is an endogenous inhibitor of mTOR and can regulate the transcriptional level of PGC-1α; PGC-1α can positively regulate SIRT3, and can also promote the expression of Sirt3 gene by mediating ERRα; SIRT3 can deacetylate FoxO3A in the mitochondrial matrix, and can also activate LKB1 to form a positive feedback loop to promote the expression of AMPK. P, phosphorylate; AC, acetylation; DAC, deacetylation.

FIGURE 2

The effect of PGC-1α on OA chondrocytes. PGC-1α enhances the expression of NRF1, NRF2 and TFAM, and promotes the biogenesis of chondrocyte mitochondria; FGF19, REDD1 and Omentin-1 promote the biogenesis of chondrocyte mitochondria by promoting the expression of PGC-1α; Sesn2 reduces the pain of OA by promoting the expression of PGC-1α and NRF2; PGC-1α and SIRT3 form a positive feedback loop to promote the expression of autophagy factor MUL1 to promote mitophagy; the increase of PGC-1α expression can promote the expression of FoxO3A and UCP2 to inhibit the production of ROS; In addition, the increase of PGC-1α can also inhibit the expression of NOX1/4 to inhibit oxidative stress; On the contrary, PKR promotes the production of TNF-α by down-regulating the expression of PGC-1α to promote the production of ROS; REDD1 and Omentin-1 through affect the level of PGC-1α to promote the expression of mtDNA; PGC-1α promotes the catabolism of fatty acids and cholesterol by regulating the activity of ATGL and LXR, and CITED2 can also promote the expression of lipocalin by activating PGC-1α to regulate chondrocyte metabolism; High levels of glucose in OA chondrocytes can down-regulate the level of PGC-1α to inhibit mitochondrial metabolism; PGC-1α can be activated by REDD1 to down-regulate the level of inflammatory cytokine TNF-α to inhibit apoptosis. The effect of PGC-1α on inhibiting apoptosis can also be realized by inhibiting ER stress. In addition, the level of PGC-1α can be regulated by AGEs, and the decrease of PGC-1α level in chondrocytes can activate BNIP3 to promote apoptosis.

FIGURE 3

Targets of action of drugs with therapeutic effects on OA by affecting the activity of PGC-1α. Quercetin, FA, MAG, geraniin, and Br in RB@MPMW promote PGC-1α expression and delay the deterioration of OA by activating the AMPK/SIRT1/PGC-1α signaling pathway; Apple Procyanidins and catalpol can affect PGC-1α activity and ameliorate mitochondrial damage in OA chondrocytes; Ginsenoside Rg3 and DHM exert anti-inflammatory and chondrocyte homeostatic effects through the PGC-1α/SIRT3 pathway; SRT1720, an activator of SIRT1, exerts chondroprotective effects by activating SIRT1 and PGC-1α; DMF enhances NRF2 expression to promote mitochondrial biogenesis in chondrocytes.