Adipocyte-Specific TMEM41B Deficiency Enhances Bone Formation and Attenuates Osteoporosis via the YY1-Calreticulin Axis

Here, we identify TMEM41B, an endoplasmic reticulum-resident protein, as a critical regulator of bone homeostasis through its actions in bone marrow adipocytes (BMAs). Adipocyte-specific deletion of TMEM41B in mice (TMEM41B AKO) significantly increased bone mass, improved trabecular and cortical bone parameters, and enhanced mechanical strength, particularly in long bones.

These effects were observed in both physiological settings and pathological models, including high-fat diet-induced osteopenia and ovariectomy-induced osteoporosis. Mechanistically, TMEM41B deficiency upregulated calreticulin (Calr) expression specifically in BMAs, which promoted osteoblast differentiation and bone formation. Mechanistically, we identified the transcription factor YY1 as a key intermediary, binding to the Calr promoter to drive its expression upon TMEM41B loss.