Ciliary Ift20 and Wwtr1 Coordinate Transforming Growth Factor-β Receptor II Signaling to Maintain Bone–Fat Balance in Skeletal Homeostasis

Abstract

The balance between bone formation and bone marrow adipose tissue accumulation is essential for skeletal integrity, and disruption of this balance contributes to skeletal degeneration, osteoporosis, and metabolic bone loss. However, the molecular mechanisms controlling this balance across skeletal homeostasis and disease remain unclear. Here, transcriptomic analysis of human osteoporotic bone samples revealed significant downregulation of Ift20 and Wwtr1 in osteoblast-lineage cells. Using osteoblast-specific knockout models, we found that loss of both Ift20 and Wwtr1 in the osteoblast lineage caused severe bone loss and excessive bone marrow adipose tissue accumulation, which was further aggravated under ovariectomy and high-fat diet conditions. Mechanistically, Ift20 localized to primary cilia and interacted with transforming growth factor-β receptor II (TβRII), protecting it from c-Cbl-mediated ubiquitination and degradation to sustain TGF-β signaling. Meanwhile, Wwtr1 directly bound the TβRII promoter to promote its transcription. Loss of Ift20 and Wwtr1 converged on TβRII suppression, impairing osteoblast differentiation while enhancing adipogenesis and osteoclastogenesis. These findings reveal a previously unrecognized cilia–transcription–TGF-β regulatory mechanism that governs osteoblast–adipocyte fate decisions and skeletal remodeling. The Ift20–Wwtr1–TβRII axis represents a critical safeguard of bone mass and marrow fat balance and may provide a therapeutic target for osteoporosis and metabolic bone diseases.