Complement Proteins C1q-C5 as Context‑Dependent Regulators of Osteoblast Function and Fracture Healing: A Systematic Review.

Background: Complement proteins (C1q-C5) participate in immune surveillance and inflammation, but their roles in osteoblast biology and fracture healing remain generally undefined. Emerging evidence suggests that complement activation may exert both pro‑regenerative and pro‑inflammatory effects, depending on receptor engagement and physiological context. Methods: A systematic review was conducted following PRISMA guidelines, using a semantic search strategy to identify studies evaluating complement components C1q-C5 in osteoblast function or fracture‑healing outcomes. 20 studies met the inclusion criteria, including rodent fracture models, in vitro osteoblast and osteoclast assays, aging and estrogen‑deficiency models, and receptor‑specific genetic manipulations. Results: Across studies, C3a/C3aR signaling consistently promoted osteoblast differentiation, migration, and early callus organization, while C3 deficiency or C3aR inhibition preserved bone formation in aging and estrogen‑deficiency states. In contrast, C5a/C5aR1 activation induced pro‑inflammatory osteoblast phenotypes, increased osteoclastogenic cytokines, and impaired matrix organization, particularly when complement activity was excessive. C5aR1 blockade had little to no effect in uncomplicated fractures, but restored healing in trauma‑induced systemic inflammation. Receptor‑specific models demonstrated that C5aR1 drives early inflammatory signaling, whereas C5aR2 modulates its resolution. Conclusions: Complement proteins act as contextual regulators of skeletal repair, supporting osteoblast-mediated regeneration under physiologic activation, while impairing healing when over-activated. These findings highlight the therapeutic potential of targeted complement modulation in inflammatory fracture environments and underscore the need for human studies to define translational applications.