Reduced Terminal Complement Complex Formation in Mice Manifests in Low Bone Mass and Impaired Fracture Healing

Am J Pathol. 2019 Jan;189(1):147-161. doi: 10.1016/j.ajpath.2018.09.011. Epub 2018 Oct 17.


The terminal complement complex (TCC) is formed on activation of the complement system, a crucial arm of innate immunity. TCC formation on cell membranes results in a transmembrane pore leading to cell lysis. In addition, sublytic TCC concentrations can modulate various cellular functions. TCC-induced effects may play a role in the pathomechanisms of inflammatory disorders of the bone, including rheumatoid arthritis and osteoarthritis. In this study, we investigated the effect of the TCC on bone turnover and repair. Mice deficient for complement component 6 (C6), an essential component for TCC assembly, and mice with a knockout of CD59, which is a negative regulator of TCC formation, were used in this study. The bone phenotype was analyzed in vivo, and bone cell behavior was analyzed ex vivo. In addition, the mice were subjected to a femur osteotomy. Under homeostatic conditions, C6-deficient mice displayed a reduced bone mass, mainly because of increased osteoclast activity. After femur fracture, the inflammatory response was altered and bone formation was disturbed, which negatively affected the healing outcome. By contrast, CD59-knockout mice only displayed minor skeletal alterations and uneventful bone healing, although the early inflammatory reaction to femur fracture was marginally enhanced. These results demonstrate that TCC-mediated effects regulate bone turnover and promote an adequate response to fracture, contributing to an uneventful healing outcome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Regeneration* / genetics
  • Bone Regeneration* / immunology
  • CD59 Antigens / deficiency
  • Cell Culture Techniques
  • Complement C6 / deficiency
  • Complement Membrane Attack Complex* / genetics
  • Complement Membrane Attack Complex* / immunology
  • Complement Membrane Attack Complex* / metabolism
  • Erythrocytes / immunology
  • Erythrocytes / metabolism
  • Erythrocytes / pathology
  • Femoral Fractures* / genetics
  • Femoral Fractures* / immunology
  • Femoral Fractures* / metabolism
  • Femoral Fractures* / pathology
  • Fracture Healing* / genetics
  • Fracture Healing* / immunology
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Osteoclasts* / immunology
  • Osteoclasts* / metabolism
  • Osteoclasts* / pathology
  • Sheep


  • CD59 Antigens
  • Complement C6
  • Complement Membrane Attack Complex