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Peer-reviewedCC BY 4.0Frontiers in Immunology

Local complement dysregulation in osteoarthritis: from C3/C5 activation to membrane attack complex–driven joint damage

  • Jianghan Zhao1
  • Gongchang Yu1
  • Bin Shi1
  1. 1Shandong Key Laboratory of Biomechanics, Neck-Shoulder and Lumbocrural Pain Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences
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Abstract

Joint inflammation can persist after the initial injury in osteoarthritis (OA). Local complement activation offers one explanation. Damaged matrix and cellular debris can activate complement, while chondrocytes and synovial cells supply some of its components. C3 and C5 cleavage then generate inflammatory mediators and initiate membrane attack complex formation. Human studies document these events in diseased joints, but most causal evidence comes from animal models and cartilage cultures. This mini review examines what that evidence supports and where the proposed feedback loop remains uncertain. We update earlier reviews with recent findings on terminal-complement-associated senescence and metabolic stress, while distinguishing OA evidence from mechanisms proposed in other diseases. We argue that terminal deposition should be interpreted alongside regulatory protection and cell viability, rather than as an isolated marker of disease activity. Likewise, complement abundance in synovial fluid cannot establish local synthesis or predict treatment response. Local terminal inhibition and restoration of regulatory protection merit further study. Experimental C5a receptor 1 (C5aR1) blockade partly reduces pain-like behavior in a chemical OA model, but sensory mechanisms and clinical benefit remain unresolved. The next step is to identify joints with persistent, damaging activation and determine whether timed intervention can interrupt it without compromising repair or host defense.

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Cite

BibTeXRIS
BibTeX
@article{zhao2026local,
  title = {{Local complement dysregulation in osteoarthritis: from C3/C5 activation to membrane attack complex–driven joint damage}},
  author = {Jianghan Zhao and Gongchang Yu and Bin Shi},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = nov,
  doi = {10.3389/fimmu.2026.2010824},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.2010824/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Local complement dysregulation in osteoarthritis: from C3/C5 activation to membrane attack complex–driven joint damage
AU  - Jianghan Zhao
AU  - Gongchang Yu
AU  - Bin Shi
PY  - 2026
DA  - 2026/11/02
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.2010824
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.2010824/full
AB  - Joint inflammation can persist after the initial injury in osteoarthritis (OA). Local complement activation offers one explanation. Damaged matrix and cellular debris can activate complement, while chondrocytes and synovial cells supply some of its components. C3 and C5 cleavage then generate inflammatory mediators and initiate membrane attack complex formation. Human studies document these events in diseased joints, but most causal evidence comes from animal models and cartilage cultures. This mini review examines what that evidence supports and where the proposed feedback loop remains uncertain. We update earlier reviews with recent findings on terminal-complement-associated senescence and metabolic stress, while distinguishing OA evidence from mechanisms proposed in other diseases. We argue that terminal deposition should be interpreted alongside regulatory protection and cell viability, rather than as an isolated marker of disease activity. Likewise, complement abundance in synovial fluid cannot establish local synthesis or predict treatment response. Local terminal inhibition and restoration of regulatory protection merit further study. Experimental C5a receptor 1 (C5aR1) blockade partly reduces pain-like behavior in a chemical OA model, but sensory mechanisms and clinical benefit remain unresolved. The next step is to identify joints with persistent, damaging activation and determine whether timed intervention can interrupt it without compromising repair or host defense.
SN  - 1664-3224
ER  -