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. 2021 Oct 5;33(10):1957-1973.e6.
doi: 10.1016/j.cmet.2021.08.009. Epub 2021 Sep 9.

Senescent immune cells release grancalcin to promote skeletal aging

Chang-Jun Li  1 , Ye Xiao  2 , Yu-Chen Sun  2 , Wen-Zhen He  2 , Ling Liu  2 , Mei Huang  2 , Chen He  2 , Min Huang  2 , Kai-Xuan Chen  2 , Jing Hou  2 , Xu Feng  2 , Tian Su  2 , Qi Guo  2 , Yan Huang  2 , Hui Peng  2 , Mi Yang  2 , Guang-Hui Liu  3 , Xiang-Hang Luo  4
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Free article

Senescent immune cells release grancalcin to promote skeletal aging

Chang-Jun Li et al. Cell Metab. .
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Erratum in

  • Senescent immune cells release grancalcin to promote skeletal aging.
    Li CJ, Xiao Y, Sun YC, He WZ, Liu L, Huang M, He C, Huang M, Chen KX, Hou J, Feng X, Su T, Guo Q, Huang Y, Peng H, Yang M, Liu GH, Luo XH. Li CJ, et al. Cell Metab. 2022 Jan 4;34(1):184-185. doi: 10.1016/j.cmet.2021.12.003. Cell Metab. 2022. PMID: 34986333 No abstract available.

Abstract

Skeletal aging is characterized by low bone turnover and marrow fat accumulation. However, the underlying mechanism for this imbalance is unclear. Here, we show that during aging in rats and mice proinflammatory and senescent subtypes of immune cells, including macrophages and neutrophils, accumulate in the bone marrow and secrete abundant grancalcin. The injection of recombinant grancalcin into young mice was sufficient to induce premature skeletal aging. In contrast, genetic deletion of Gca in neutrophils and macrophages delayed skeletal aging. Mechanistically, we found that grancalcin binds to the plexin-b2 receptor and partially inactivates its downstream signaling pathways, thus repressing osteogenesis and promoting adipogenesis of bone marrow mesenchymal stromal cells. Heterozygous genetic deletion of Plexnb2 in skeletal stem cells abrogated the improved bone phenotype of Gca-knockout mice. Finally, we developed a grancalcin-neutralizing antibody and showed that its treatment of older mice improved bone health. Together, our data suggest that grancalcin could be a potential target for the treatment of age-related osteoporosis.

Keywords: bone marrow mesenchymal stromal cells; bone remodeling; grancalcin; immune cells; immunoregulation; linage fate; plexin-b2 pathway; senescence; skeletal aging.

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Conflict of interest statement

Declaration of interests X-H.L. and C.-J.L. disclose that they are inventors of a submitted patent application by Xiangya Hospital of Central South University covering GCA-neutralizing antibody (GCA-NAb). All other authors declare no competing financial interests.

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