ERα/β/DMP1 axis promotes trans‐differentiation of chondrocytes to bone cells through GSK‐3β/β‐catenin pathway

Abstract

Estrogen‐induced premature closing of the growth plate in the long bones is a major cause of short stature after premature puberty. Recent studies have found that chondrocytes can directly trans‐differentiate into osteoblasts in the process of endochondral bone formation, which indicates that cartilage formation and osteogenesis may be a continuous biological process. However, whether estrogen promotes the direct trans‐differentiation of chondrocytes into osteoblasts remains largely unknown. Chondrocytes were treated with different concentrations of 17β‐estradiol, and Alizarin Red staining and alkaline phosphatase activity assay were used to detected osteogenesis. Specific short hairpin RNA and tamoxifen were used to block the estrogen receptor (ER) pathway and osteogenic marker genes and downstream gene expression were detected using real‐time quantitative polymerase chain reaction, western blot, and immunohistochemistry staining. The findings showed that 17β‐estradiol promoted the chondrocyte osteogenesis in vitro, even at high concentrations. In addition, blocking of the ERα/β pathway inhibited the trans‐differentiation of chondrocytes into osteogenic cells. Furthermore, we found that dentin matrix protein 1 (DMP1), which is a direct downstream molecular of ER, was involved in 17β‐estradiol/ER pathway‐regulated osteogenesis. As well, glycogen synthase kinase‐3 beta (GSK‐3β)/β‐catenin signal pathway also participates in ERα/β/DMP1‐regulated chondrocyte osteogenesis. The GSK‐3β/β‐catenin signal pathway was involved in ERα/β/DMP1‐regulated chondrocyte osteogenesis. These findings suggest that ER/DMP1/GSK‐3β/β‐catenin plays a vital role in estrogen regulation of chondrocyte osteogenesis and provide a therapeutic target for short stature caused by epiphyseal fusion.

Single-cell RNA sequencing analysis of the temporomandibular joint condyle in 3 and 4-month-old human embryos

“…In addition, we explored other signaling pathways between TSCs, hypertrophic chondrocytes and osteoblasts. Notably, we screened many chondrocyte and osteoblast differentiation signaling pathways, including PTN [ 18 ], BMP [ 19 ], TENASCIN [ 46 ], ACTIVIN [ 47 ], RANKL [ 47 ], DMP1 [ 48 ], MK [ 49 ], FGF [ 20 ], GRN [ 50 ], CXCL [ 21 ], MSTN [ 22 ] and GH [ 23 ]. These reported signaling pathways regulating bone differentiation may also play an important role in the differentiation of TSCs, hypertrophic chondrocytes and osteoblasts.…”

The cell developmental atlas of human embryonic temporomandibular joint

“…In addition, we also explored other signaling pathways among TSCs, hypertrophic chondrocytes and osteoblasts. Notably, many differentiation signaling pathways of chondrocytes and osteoblasts were screened including PTN 13 , BMP 14 , TENASCIN 32 , ACTIVIN 33 , RANKL 33 , DMP1 34 , MK 35 , FGF 15 , GRN 36 , CXCL 16 , MSTN 17 and GH 18 . These reported signaling pathways regulating bone differentiation may also play important roles in the differentiation of TSCs, hypertrophic chondrocytes and osteoblasts.…”