Work

WTAP Transcriptional Suppression by KLF9 Drives Osteoclastogenesis via M 6 A‐Mediated Regulation of CSF1R Signaling in Estrogen‐Deficient Osteoporosis

Year: 2026

Type: article

Abstract: ABSTRACT Osteoporosis, characterized by imbalanced bone homeostasis, is driven by excessive osteoclast‐mediated bone resorption, yet the epitranscriptomic regulation via m 6 A modification remains unclear. Here, we identify WTAP, a component of the m 6 A methyltransferase complex, as a critical negative regulator of osteoclastogenesis. Myeloid‐specific Wtap knockout in mice exacerbates osteoclast formation and osteoporotic bone loss. Mechanistically, WTAP mediates m 6 A deposition on Csflr mRNA, promoting degradation via the key m 6 A reader YTHDF2 and downregulating CSF1R expression, thereby enhancing osteoclastogenesis and bone loss in estrogen‐deficient osteoporosis. We further discover that KLF9, induced during osteoclast differentiation, translocates to the nucleus to directly repress Wtap transcription, initiating this pathological process. Concurrent conditional knockout of KLF9 in osteoclast precursors rescues the exacerbated osteoporotic bone loss driven by myeloid‐specific Wtap deficiency in vivo. This KLF9/WTAP/YTHDF2/m 6 A/CSF1R axis establishes a novel epigenetic circuit regulating bone resorption. Therapeutically, targeting this axis via AAV‐mediated Wtap overexpression or pharmacological CSF1R inhibition with pexidartinib effectively ameliorates bone loss in osteoporotic mice. Our findings elucidate a previously unrecognized epitranscriptomic mechanism controlling osteoclastogenesis and highlight its therapeutic potential for pathological bone resorption.

Source: Advanced Science

DOI: 10.1002/advs.77227