Targeting injury-triggered grancalcin from senescent macrophages enhances aged bone healing.

Yangjiele Dong, Xin Shen, Qianwei Zhuang, Shenghao Jin, Zesheng Song, Ziji Ling, Hongbing Jiang

Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China; State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases (Nanjing Medical University), China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine ( Nanjing Medical University), China.Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China; State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases (Nanjing Medical University), China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine ( Nanjing Medical University), China. · pubmed

Paper

Abstract

Age-related decline in bone regenerative capacity poses a significant challenge for craniofacial skeleton repair in elderly patients. Grancalcin (GCA), a calcium-binding protein secreted by myeloid cells, has been identified as a potential contributor to the process of skeletal aging. However, its specific role in age-related craniofacial bone regeneration remains poorly understood. Using a mouse model of tooth extraction socket healing, we show that GCA from bone marrow-derived macrophages (BMDMs) regulates both cellular senescence and osteogenic differentiation of bone marrow stromal cells (BMSCs) during bone regeneration in aged mice. Mechanistically, the injury-responsive transcription factors c-Jun and SPI1 act synergistically to drive Gca expression in senescent BMDMs, thereby impairing mitochondrial function and osteogenesis in BMSCs via the Plxnb2-Arg2 axis. Furthermore, we engineered a gelatin methacryloyl (GelMA) hydrogel for the sustained local delivery of a GCA-neutralizing antibody (GelMA-GCA-NAb). Local application of this hydrogel markedly enhanced jaw bone healing in aged mice. Our findings identify injury-induced GCA as a key mediator connecting immune senescence to deficient bone regeneration and propose local GCA neutralization via hydrogel as a promising immunotherapeutic strategy to improve bone healing in the elderly. STATEMENT OF SIGNIFICANCE: Current conventional therapies for age-related bone healing face limitations in addressing aging-impaired biological processes, while hydrogels delivering targeted factors show significant promise by enabling precise modulation of the local microenvironment. This study reveals that c-Jun/SPI1-driven GCA from senescent macrophages promotes BMSCs senescence and impairs osteogenesis via Plxnb2-Arg2 in age-related jawbone injury. Importantly, local delivery of a GCA-neutralizing antibody via GelMA hydrogel accelerates healing, offering an emerging therapeutic strategy.

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Research summary

The paper claims that targeting injury-triggered grancalcin from senescent macrophages can enhance aged bone healing. This research addresses a mechanism related to age-related decline in bone regeneration, which is a fundamental aspect of aging and longevity.

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