Complement C3a and C5a modulate osteoclast formation and inflammatory response of osteoblasts in synergism with IL-1β

J Cell Biochem. 2011 Sep;112(9):2594-605. doi: 10.1002/jcb.23186.


There is a tight interaction of the bone and the immune system. However, little is known about the relevance of the complement system, an important part of innate immunity and a crucial trigger for inflammation. The aim of this study was, therefore, to investigate the presence and function of complement in bone cells including osteoblasts, mesenchymal stem cells (MSC), and osteoclasts. qRT-PCR and immunostaining revealed that the central complement receptors C3aR and C5aR, complement C3 and C5, and membrane-bound regulatory proteins CD46, CD55, and CD59 were expressed in human MSC, osteoblasts, and osteoclasts. Furthermore, osteoblasts and particularly osteoclasts were able to activate complement by cleaving C5 to its active form C5a as measured by ELISA. Both C3a and C5a alone were unable to trigger the release of inflammatory cytokines interleukin (IL)-6 and IL-8 from osteoblasts. However, co-stimulation with the pro-inflammatory cytokine IL-1β significantly induced IL-6 and IL-8 expression as well as the expression of receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) indicating that complement may modulate the inflammatory response of osteoblastic cells in a pro-inflammatory environment as well as osteoblast-osteoclast interaction. While C3a and C5a did not affect osteogenic differentiation, osteoclastogenesis was significantly induced even in the absence of RANKL and macrophage-colony stimulating factor (M-CSF) suggesting that complement could directly regulate osteoclast formation. It can therefore be proposed that complement may enhance the inflammatory response of osteoblasts and increase osteoclast formation, particularly in a pro-inflammatory environment, for example, during bone healing or in inflammatory bone disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Cell Differentiation
  • Cells, Cultured
  • Complement C3a / metabolism
  • Complement C3a / pharmacology*
  • Complement C3a / physiology
  • Complement C5a / metabolism
  • Complement C5a / pharmacology*
  • Complement C5a / physiology
  • Gene Expression
  • Humans
  • Inflammation
  • Interleukin-1beta / pharmacology*
  • Interleukin-1beta / physiology
  • Male
  • Mesenchymal Stem Cells / metabolism
  • Mesenchymal Stem Cells / physiology
  • Microscopy, Fluorescence
  • Osteoblasts / metabolism
  • Osteoblasts / physiology*
  • Osteoclasts / metabolism
  • Osteoclasts / physiology*
  • Osteogenesis
  • Osteoprotegerin / metabolism
  • Proteolysis
  • RANK Ligand / metabolism
  • Receptors, Complement / genetics
  • Receptors, Complement / metabolism
  • Young Adult


  • Antigens, CD
  • Interleukin-1beta
  • Osteoprotegerin
  • RANK Ligand
  • Receptors, Complement
  • TNFSF11 protein, human
  • Complement C3a
  • Complement C5a