SETD7 regulates chondrocyte differentiation and glycolysis via the Hippo signaling pathway and HIF‑1α

Abstract

Chondrocytes are well adapted to hypoxia and produce more functional extracellular matrix in low oxygen environments in vitro . In our previous study, methyltransferase SET domain containing (SETD)7 regulated chondrocyte activity in hypoxic conditions. However, the precise association between SETD7 and chondrocyte differentiation under low oxygen partial pressure remains unclear. The association between SETD7 and chondrocyte differentiation was studied by silencing SETD7 in chondrocytes in vitro . The results showed that the silencing of SETD7 in ATDC5 cells inhibited the Hippo signaling pathway, decreased Yes-associated protein (YAP) phosphorylation and increased the levels of YAP and hypoxia inducible factor-1α (HIF-1α) in the nucleus. YAP combined with HIF-1α to form a complex that promoted the expression of genes involved in chondrogenic differentiation and the glycolytic pathway. Thus, SETD7 inhibited chondrocyte differentiation and glycolysis via the Hippo signaling pathway. The present study demonstrated that SETD7 was a potential molecular target that maintained the chondrocyte phenotype during cartilage tissue engineering and cartilage-associated disease.

Aspirin reverses inflammatory suppression of chondrogenesis by stabilizing YAP

“…Furthermore, Nie et al 38 found that dasatinib promoted the chondrogenic differentiation of mesenchymal stem cells by increasing the phosphorylation level of YAP. In addition to regulating the chondrogenic differentiation of stem cells, YAP has been shown to play a key role in the chondrogenesis of C3H10T1/2 and ATDC5 cells 39–41 . Taken together, YAP plays an essential regulatory role in the process of chondrogenesis in various cell types.…”

“…Furthermore, Nie et al 38 and ATDC5 cells. [39][40][41] Taken together, YAP plays an essential regulatory role in the process of chondrogenesis in various cell types.…”

“…In addition to regulating the chondrogenic differentiation of stem cells, YAP has been shown to play a key role in the chondrogenesis of C3H10T1/2 and ATDC5 cells. 39 , 40 , 41 Taken together, YAP plays an essential regulatory role in the process of chondrogenesis in various cell types.…”

Maintaining hypoxia environment of subchondral bone alleviates osteoarthritis progression

“…In recent years, HIF-1α has been recognized as a protective factor in maintaining normal chondrocyte function, mainly through promoting chondrocyte metabolism, differentiation, and matrix secretion (39)(40)(41). HIF-1α serves as a pivotal factor for chondrocytes by maintaining anaerobic glycolysis and impeding apoptosis via mitophagy (42,43). HIF-1α is also a positive regulator for the expression of SRY-Box Transcription Factor 9 (SOX9), COL2A1, and ACAN and inhibits the expression of COL1A1, COL1A2, COL10A1, and MMP13 to promote chondrocyte differentiation and matrix synthesis (40,(44)(45)(46).…”

The Epigenetic Regulation of Nonhistone Proteins by SETD7: New Targets in Cancer

“…Interestingly, SETD7 expression is suppressed under hypoxic conditions ( Liu et al, 2015 ). Others have reported that SETD7 is a negative regulator of HIF-1α and downregulates HIF-1α target genes, such as GLUT1, LDHA, PGK1, EPO, PKM2 and VEGF, which are upregulated after SETD7 inhibition ( Li et al, 2021 ; Xiaoshi et al, 2021 ).…”