2. Academic Validation
  3. Osteocytes Produces RANKL Via Wnt-TGFβ Signaling Axis for Osteoclastogenesis

Osteocytes Produces RANKL Via Wnt-TGFβ Signaling Axis for Osteoclastogenesis

  • Int J Biol Sci. 2025 Sep 12;21(13):5821-5841. doi: 10.7150/ijbs.117481.
Yujiao Liu 1 2,  Lizhou Zhao 1,  Molin Li 1,  Weimin Gong 1,  Xiaofang Wang 1,  Yu Cheng 3,  Ying Zhang 1,  Pengtao Wang 1,  Yisheng Luo 1,  Yining Zhang 1,  Yufei Shao 4,  Makoto Mark Taketo 5,  Teresita Bellido 6,  Gaohai Shao 2,  Xing Liu 4,  Xiaolin Tu 1 7
Affiliations

Affiliations

  • 1 Laboratory of Skeletal Development and Regeneration, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China.
  • 2 Department of Orthopedics, Affiliated Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, China.
  • 3 Department of Nursing, Affiliated University City Hospital of Chongqing Medical University, Chongqing 401331, China.
  • 4 Department of Orthopedics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
  • 5 Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan.
  • 6 Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72223, USA.
  • 7 Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
PMID: 41079923 DOI: 10.7150/ijbs.117481
Abstract

Osteocytes are derived from osteoblasts in the mineralized matrix and are the main source of RANKL required for osteoclastogenesis. We initially found osteocytes as central target cells for Wnt/β-catenin signaling that increases RANKL expression and bone resorption in mice. However, how RANKL is regulated remains unclear. Here, we demonstrated its role and molecular mechanisms using primary osteocytes isolated from long bones. Osteocyte transcriptome Sequencing revealed the most associated osteoclast differentiation in KEGG pathways with upregulated expression of Tgfb1/2. In vivo data highlight the specificity of osteocytic Wnt, rather than osteoblastic Wnt, in regulating TGFβ signaling. Activation/inactivation of osteocytic TGFβ signaling stringently promotes/inhibits RANKL expression and osteoclast differentiation in dose- and time-dependent manners. Wnt signaling increases RANKL expression through TGFβ signaling via the physical interaction of its transcription factor SMAD4 with the RANKL promoter region. Mice with disrupted TGFβ signaling in osteocytes recapitulate defective osteoclastogenesis and reduced RANKL expression in osteocytes. Thus, osteocytes mediate bone resorption via Wnt-TGFβ signaling axis.

Keywords

Osteocyte; RANKL; TGFβ; Wnt/β-catenin; osteoclastogenesis.

Figures
Products