MAGP2 promotes osteogenic differentiation during fracture healing through its crosstalk with the β‐catenin pathway

Abstract Osteogenic differentiation is important for fracture healing. Microfibrial‐associated glycoprotein 2 (MAGP2) is found to function as a proangiogenic regulator in bone formation; however, its role in osteogenic differentiation during bone repair is not clear. Here, a mouse model of critical‐sized femur fracture was constructed, and the adenovirus expressing MAGP2 was delivered into the fracture site. Mice with MAGP2 overexpression exhibited increased bone mineral density and bone volume fraction (BV/TV) at Day 14 postfracture. Within 7 days postfracture, overexpression of MAGP2 increased collagen I and II expression at the fracture callus, with increasing chondrogenesis. MAGP2 inhibited collagen II level but elevated collagen I by 14 days following fracture, accompanied by increased endochondral bone formation. In mouse osteoblast precursor MC3T3‐E1 cells, MAGP2 treatment elevated the expression of osteoblastic factors (osterix, BGLAP and collagen I) and enhanced ALP activity and mineralization through activating β‐catenin signaling after osteogenic induction. Besides, MAGP2 could interact with lipoprotein receptor‐related protein 5 (LRP5) and upregulated its expression. Promotion of osteogenic differentiation and β‐catenin activation mediated by MAGP2 was partially reversed by LRP5 knockdown. Interestingly, β‐catenin/transcription factor 4 (TCF4) increased MAGP2 expression probably by binding to MAGP2 promoter. These findings suggest that MAGP2 may interact with β‐catenin/TCF4 to enhance β‐catenin/TCF4's function and activate LRP5‐activated β‐catenin signaling pathway, thus promoting osteogenic differentiation for fracture repair. mRNA sequencing identified the potential targets of MAGP2, providing novel insights into MAGP2 function and the directions for future research.