Fig. 1: Different transcription factors regulate three different differentiation fates — adipocytes, osteoblasts, and chondrocytes from MSCs.

MSCs have three different differentiation fates — adipocytes, osteoblasts, and chondrocytes — which are regulated by different genes. In the differentiation process, some cells in the three differentiation pathways also have a reciprocal transformation relationship through the regulation of related genes, such as interactions between mature osteoblasts and mature osteoclasts or hypertrophic chondrocytes and early osteoblasts. Transcription factors have different functions in different stages of osteoblast differentiation. Runx2 is a vital factor in all osteoblast differentiation stages; Runx2 promotes osteoblast differentiation in the early stage while inhibiting mature osteoblast differentiation into osteocytes. Cbfβ is the major co-factor of Runx2 and Runx1. Runx3 can promote chondrocytes into hypertrophic chondrocytes. SIRT1 and FOXO1 can promote Runx2 expression. Osx and β-catenin also have important functions in the early stage of osteoblast differentiation. SATB2 and ATF4 are important in promoting the terminal differentiation stage of osteoblast. SATB2 inhibits Hoxa2 activity in the early stage of osteoblast differentiation. Runx1 plays an important role in inhibiting adipocyte differentiation and promoting chondrocyte differentiation. The interaction between osteoblasts and osteoclasts is also very important. Osteoblasts regulate osteoclast differentiation via RANKL signaling and inhibit osteoclast differentiation through OPG. Similarly, osteoclasts can regulate osteoblast differentiation through the Wnt10b, BMP6, or Ephrin signaling pathway.