Journal News

Receptor antagonist reduces age-related bone loss in mice

Emily Ulrich
Aug. 6, 2025

Bone remodeling involves a regulation between osteoblasts for bone formation and osteoclasts for bone resorption, and this process shifts out of balance with age and with the development of osteoporosis. The complement system, activated as part of the innate immune response to infection, also functions in bone development. The G protein-coupled receptor C3aR is expressed as a component of the complement system in bone marrow cells. Fangyu Li and Shun Cui at Huazhong University of Science and Technology investigated whether C3aR plays a role in age-related impacts on bone remodeling. They published their recent findings in the Journal of Biological Chemistry.

3D rendering of the three stages of osteoporosis featuring progressive bone loss.
3D rendering of the three stages of osteoporosis featuring progressive bone loss.

The researchers first noted that C3aR expression trends upward as mice age, in conjunction with higher levels of senescence markers. In contrast, mice with C3aR knocked out showed an increase in bone mass compared to a control group of the same age. The C3aR knockout mice also exhibited higher expression of the osteogenic marker osteoprotegerin and lower expression of the osteoclast marker tartaric acid resistance phosphatase, suggesting a shift toward bone formation over resorption.

In addition, the authors tested a C3aR antagonist, called JR14a, in cells treated with D-galactose to mimic cell damage caused by aging  and found that the antagonist restored cell viability. They applied JR14a to a mouse model, and their histologic staining showed an increase in osteoblasts and a decrease in osteoclasts, suggesting partial inhibition of bone loss.

Fluorescence labeling experiments performed in this study indicated that JR14a initiates YAP1/β-catenin signaling, a pathway known to promote osteoblast differentiation. Future studies will help determine the details of downstream effects caused by C3aR inhibition and the possibility of targeting C3aR for relieving age-related dysfunction in bone remodeling.

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Emily Ulrich

Emily Ulrich is the ASBMB’s science editor.

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