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<p>Postmenopausal osteoporosis (PMOP) develops within a complex metabolic milieu, but the adipose-derived cues that regulate osteoblast function are not fully defined. Here, plasma ELISA analysis showed preferential elevation of circulating C-type lectin domain family 3 member B (CLEC3B) in the high-BMI PMOP subgroup. CLEC3B was enriched in adipose tissue and negatively regulated by estradiol. <i>In vivo</i>, adipose-targeted overexpression of <i>Clec3b</i> increased trabecular bone mass and promoted osteoblast-associated bone formation without markedly altering osteoclast-related parameters. To investigate the underlying mode of action, we used an adipocyte–osteoblast conditioned-medium model. Conditioned medium from <i>Clec3b</i>-overexpressing adipocytes promoted osteogenic differentiation of primary calvarial osteoblasts, whereas conditioned medium from <i>Clec3b</i>-silenced adipocytes produced the opposite effect. Adipocyte transcriptomic analysis nominated Igfbp4 as a secretome-associated candidate reduced after <i>Clec3b</i> overexpression. Recombinant insulin-like growth factor-binding protein 4 (IGFBP4) reduced the increases in osteogenic gene expression, RUNX2 abundance, and matrix deposition induced by <i>Clec3b</i>-enriched conditioned medium. In parallel, recombinant IGFBP4 (rIGFBP4) partially attenuated the associated changes in mitochondrial superoxide-related fluorescence, intracellular oxidative fluorescence, mitochondrial membrane potential, and PINK1/PRKN-related signaling. Collectively, the data are consistent with a model whereby adipose-derived CLEC3B promotes osteogenesis through a CLEC3B–IGFBP4-related paracrine axis associated with mitochondrial adaptation in osteoblasts. These findings define a testable adipose-to-bone signaling mechanism relevant to osteoblast dysfunction in PMOP.</p> Graphical Abstract <p>Proposed adipose-to-bone CLEC3B–IGFBP4-related paracrine axis associated with mitochondrial adaptation in osteoblasts.</p> <p>• Plasma CLEC3B is preferentially elevated in high-BMI PMOP.</p> <p>• Adipose-targeted <i>Clec3b</i> overexpression promotes trabecular bone accrual.</p> <p>• Adipocytic <i>Clec3b</i> overexpression suppresses IGFBP4 and enhances osteogenic differentiation.</p> <p>• The CLEC3B–IGFBP4-related axis is associated with mitochondrial adaptation in osteoblasts.</p> <p></p>

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Adipose-derived CLEC3B promotes osteogenesis through a CLEC3B–IGFBP4-related paracrine axis associated with mitochondrial adaptation in postmenopausal osteoporosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月3日

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  • Zhihao Xia,
  • Liangliang Wei,
  • Jiajia Ji,
  • Shaobo Wu,
  • Yue Sun,
  • Gaoyang Zong,
  • Xiangyang Li,
  • Yuxing Ye,
  • Yan Zhang,
  • Dageng Huang

摘要

Postmenopausal osteoporosis (PMOP) develops within a complex metabolic milieu, but the adipose-derived cues that regulate osteoblast function are not fully defined. Here, plasma ELISA analysis showed preferential elevation of circulating C-type lectin domain family 3 member B (CLEC3B) in the high-BMI PMOP subgroup. CLEC3B was enriched in adipose tissue and negatively regulated by estradiol. In vivo, adipose-targeted overexpression of Clec3b increased trabecular bone mass and promoted osteoblast-associated bone formation without markedly altering osteoclast-related parameters. To investigate the underlying mode of action, we used an adipocyte–osteoblast conditioned-medium model. Conditioned medium from Clec3b-overexpressing adipocytes promoted osteogenic differentiation of primary calvarial osteoblasts, whereas conditioned medium from Clec3b-silenced adipocytes produced the opposite effect. Adipocyte transcriptomic analysis nominated Igfbp4 as a secretome-associated candidate reduced after Clec3b overexpression. Recombinant insulin-like growth factor-binding protein 4 (IGFBP4) reduced the increases in osteogenic gene expression, RUNX2 abundance, and matrix deposition induced by Clec3b-enriched conditioned medium. In parallel, recombinant IGFBP4 (rIGFBP4) partially attenuated the associated changes in mitochondrial superoxide-related fluorescence, intracellular oxidative fluorescence, mitochondrial membrane potential, and PINK1/PRKN-related signaling. Collectively, the data are consistent with a model whereby adipose-derived CLEC3B promotes osteogenesis through a CLEC3B–IGFBP4-related paracrine axis associated with mitochondrial adaptation in osteoblasts. These findings define a testable adipose-to-bone signaling mechanism relevant to osteoblast dysfunction in PMOP.

Graphical Abstract

Proposed adipose-to-bone CLEC3B–IGFBP4-related paracrine axis associated with mitochondrial adaptation in osteoblasts.

• Plasma CLEC3B is preferentially elevated in high-BMI PMOP.

• Adipose-targeted Clec3b overexpression promotes trabecular bone accrual.

• Adipocytic Clec3b overexpression suppresses IGFBP4 and enhances osteogenic differentiation.

• The CLEC3B–IGFBP4-related axis is associated with mitochondrial adaptation in osteoblasts.