Osteoporosis is a prevalent skeletal disorder characterized by excessive bone marrow adiposity and impaired osteogenesis. Here, we identify TMEM41B, an endoplasmic reticulum-resident protein, as a critical regulator of bone homeostasis through its actions in bone marrow adipocytes. 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. We further demonstrated that TMEM41B interacted with the transcription factor YY1 to suppress its activity, and loss of TMEM41B released YY1, enabling it to bind to the calreticulin promoter and drive its expression. Chromatin accessibility profiling revealed enhanced osteogenic and suppressed adipogenic gene accessibility in TMEM41B AKO mice, while proteomic and transcriptomic analyses highlighted calreticulin as a paracrine mediator of bone marrow adipocyte–osteoblast crosstalk. Our findings establish TMEM41B as a potential therapeutic target for bone loss across both metabolic stress-associated osteopenia and estrogen deficiency-associated osteoporosis, with its inhibition in bone marrow adipocytes rescuing bone deterioration through the YY1–calreticulin axis.
Kong et al. (Fri,) studied this question.