Scara5 as a cell fate determinant of osteoblasts and adipocytes

Bone loss disorders associated with an imbalance in osteoblast and adipocyte differentiation, such as osteoporosis, are fast-growing health challenges in our aging populations. Cell fate differentiation shifts towards fat-storing adipocytes at the expense of bone-forming osteoblasts resulting in bone loss and increased fat mass. There is published evidence that murine models lacking specific scavenger receptors show alterations in bone and metabolic phenotypes. Herein, mice lacking scavenger receptor class A member 5 (Scara5) exhibited significantly greater bone mass and markedly reduced bone marrow adipose tissue than control WT animals. This was consistent with in vitro differentiation of Scara5-deficient (Scara5-/-) bone marrow stromal cells (BMSCs), showing a reduction in adipocyte differentiation and an increase in osteoblast bone nodule formation. The underlying mechanism was investigated using recombinant SCARA5 and bone-related ligands, including ferritin, HMGB1, and WNT-related proteins. These in vivo and in vitro findings underscore the crucial role of Scara5 in BMSC lineage allocation and demonstrate that Scara5 is a negative regulator of bone mass and osteogenesis. Additionally, Scara5-/- animals carried leaner body mass and a smaller percentage of subcutaneous inguinal fat than the age and sex-matched controls. This project proposes Scara5 as an important modulator of bone and adipocyte formation, which could be reciprocally manipulated as a potential therapeutic target for body fat and bone formation.