WTAP Transcriptional Suppression by KLF9 Drives Osteoclastogenesis via M6A‐Mediated Regulation of CSF1R Signaling in Estrogen‐Deficient Osteoporosis
- 1Department of Orthopedics The First Affiliated Hospital of Soochow University Suzhou Jiangsu China
- 2Department of Cardiology The First Affiliated Hospital of Soochow University Suzhou Jiangsu China
Abstract
Osteoporosis, characterized by imbalanced bone homeostasis, is driven by excessive osteoclast‐mediated bone resorption, yet the epitranscriptomic regulation via m6A modification remains unclear. Here, we identify WTAP, a component of the m6A 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 m6A deposition on Csflr mRNA, promoting degradation via the key m6A 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/m6A/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.
Related
- cBAF drives AR-V7 expression through regulation of transcriptional termination in castration-resistant prostate cancer
- Young plasma-derived exosomes deliver YOD1 to induce M2 polarization and ameliorate osteoporosis via mTOR signaling pathways.
- ARG2 drives osteoblast senescence by repressing mitophagy via the IκB-NF-κB-TXN2 signaling axis: implications for age-associated osteoporosis.
- The Cx43/p38 MAPK/Runx2 signaling pathway as a potential regulatory axis in insufficient osteogenesis associated with osteoporosis
- Liquid-liquid phase separation and post-transcriptional regulation intersection: A new paradigm of RNA-binding protein condensates in hepatocellular carcinoma malignant phenotypes (Review)
BibTeX
@article{shen2026wtap,
title = {{WTAP Transcriptional Suppression by KLF9 Drives Osteoclastogenesis via M6A‐Mediated Regulation of CSF1R Signaling in Estrogen‐Deficient Osteoporosis}},
author = {Chen Shen and Xin Liu and Gaoran Ge and Li Xu and Ziyu Zhang and Chang Lv and Hao Xu and Wenhao Li and Yi Qin and Qifeng Sheng and Qihan Wang and Hongxia Li and Jun Zhou and Huilin Yang and Dechun Geng},
journal = {Advanced Science},
year = {2026},
month = aug,
doi = {10.1002/advs.77227},
url = {https://doi.org/10.1002/advs.77227},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - WTAP Transcriptional Suppression by KLF9 Drives Osteoclastogenesis via M6A‐Mediated Regulation of CSF1R Signaling in Estrogen‐Deficient Osteoporosis
AU - Chen Shen
AU - Xin Liu
AU - Gaoran Ge
AU - Li Xu
AU - Ziyu Zhang
AU - Chang Lv
AU - Hao Xu
AU - Wenhao Li
AU - Yi Qin
AU - Qifeng Sheng
AU - Qihan Wang
AU - Hongxia Li
AU - Jun Zhou
AU - Huilin Yang
AU - Dechun Geng
PY - 2026
DA - 2026/08/30
JO - Advanced Science
DO - 10.1002/advs.77227
UR - https://doi.org/10.1002/advs.77227
AB - Osteoporosis, characterized by imbalanced bone homeostasis, is driven by excessive osteoclast‐mediated bone resorption, yet the epitranscriptomic regulation via m6A modification remains unclear. Here, we identify WTAP, a component of the m6A 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 m6A deposition on Csflr mRNA, promoting degradation via the key m6A 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/m6A/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.
SN - 2198-3844
ER -