APPL1 negatively regulates bone mass, possibly by controlling the fate of bone marrow mesenchymal progenitor cells.

Adiponectin is an adipokine that can exert a regulatory function on bone metabolism. However, there are many contradictions between clinical and pre-clinical studies on adiponectin. APPL1 is an adaptor protein that can interact with adiponectin receptors. In the current study, we found that knockout of the Appl1 gene in male mice was associated with higher bone volume and numbers of trabeculae than in females or controls. The trabecular thickness, cortical thickness, ratio of bone volume/trabecular volume, cross-sectional bone area, and mean polar moment of inertia increased in Appl1 KO mice compared with wild-type mice. The number of osteoblasts increased but the number of adipocytes decreased in Appl1 KO mice. Knockdown of Appl1 impaired adipogenesis in bone marrow-derived mesenchymal stem cells. Mineralization was increased by knockdown of Appl1 during osteoblast differentiation. Data from differentiation-related genes showed results consistent with the in vivo effects. In summary, this study provides further clarification of the effect of the adiponectin signaling pathway on bone metabolism.