WTAP Transcriptional Suppression by KLF9 Drives Osteoclastogenesis via MA‐Mediated Regulation of CSF1R Signaling in Estrogen‐Deficient Osteoporosis
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
ABSTRACT Osteoporosis, characterized by imbalanced bone homeostasis, is driven by excessive osteoclast‐mediated bone resorption, yet the epitranscriptomic regulation via mA modification remains unclear. Here, we identify WTAP, a component of the mA 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 mA deposition on Csflr mRNA, promoting degradation via the key mA 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/mA/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. Scheme of the KLF9/W
Abstract
ABSTRACT Osteoporosis, characterized by imbalanced bone homeostasis, is driven by excessive osteoclast‐mediated bone resorption, yet the epitranscriptomic regulation via mA modification remains unclear. Here, we identify WTAP, a component of the mA 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 mA deposition on Csflr mRNA, promoting degradation via the key mA 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/mA/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. Scheme of the KLF9/WTAP/YTHDF2/mA/CSF1R regulatory axis in osteoclastogenesis and estrogen‐deficient osteoporosis. WTAP‐mediated mA modification of Csf1r mRNA governs osteoclastogenesis via a YTHDF2‐mediated pathway. Pathological upregulation of KLF9 drives Wtap transcription, leading to increased mA deposition on the 3’‐UTR of Csf1r mRNA. This reduces YTHDF2 binding affinity, destabilizing Csf1r mRNA and elevating CSF1R protein levels upon M‐CSF stimulation, thereby enhancing osteoclastogenesis and promoting bone resorption. Conversely, therapeutic inhibition of KLF9 or WTAP decreases mA modification on CSF1R, restores YTHDF2 binding, stabilizes Csf1r mRNA, and reduces CSF1R expression, ultimately suppressing osteoclast differentiation. Pharmacological blockade of CSF1R with PLX3397 further attenuates osteoclastogenesis, providing a strategy to alleviate estrogen‐deficient osteoporosis. advs77227-abs-0001 graphical