Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin

Abstract

Autoimmunity is complicated by bone loss. In human rheumatoid arthritis (RA), the most severe inflammatory joint disease, autoantibodies against citrullinated proteins are among the strongest risk factors for bone destruction. We therefore hypothesized that these autoantibodies directly influence bone metabolism. Here, we found a strong and specific association between autoantibodies against citrullinated proteins and serum markers for osteoclast-mediated bone resorption in RA patients. Moreover, human osteoclasts expressed enzymes eliciting protein citrullination, and specific N-terminal citrullination of vimentin was induced during osteoclast differentiation. Affinity-purified human autoantibodies against mutated citrullinated vimentin (MCV) not only bound to osteoclast surfaces, but also led to robust induction of osteoclastogenesis and boneresorptive activity. Adoptive transfer of purified human MCV autoantibodies into mice induced osteopenia and increased osteoclastogenesis. This effect was based on the inducible release of TNF-α from osteoclast precursors and the subsequent increase of osteoclast precursor cell numbers with enhanced expression of activation and growth factor receptors. Our data thus suggest that autoantibody formation in response to citrullinated vimentin directly induces bone loss, providing a link between the adaptive immune system and bone.

Osteoimmunology: from mice to humans

“…Positivity for anti-citrullinated protein antibodys is a strong predictor of bone erosions in RA, and anti-citrullinated protein antibodys bind to OCs and stimulate OC-mediated bone resorption by increasing the production of TNF-a, IL-8, and RANKL. [25][26][27] Clinically the activation of the immune system and increased inflammation in RA correlate with joint erosions, bone mineral density, and vertebral fractures. 28 In RA the inflammatory milieu increases OC formation and activity both locally and systemically.…”

Peptidylarginine deiminase and protein citrullination in prion diseases

“…34 A recent study suggests that autoantibody production in response to citrullinated vimentin directly induces bone loss by increasing osteoclastogenesis. 44 The 18.5 kDa isoform of MBP, which is a major component of the myelin sheath, generally undergoes the citrullination of 6 of its 19 total arginine residues. While the citrullinated form normally accounts for approximately 20% of the total MBP in a healthy human brain, in MS patients, the proportion has been found to be increased to 45%.…”

The roles of immune cells in bone healing; what we know, do not know and future perspectives

“…Excessively activated NK cells could mediate cytotoxicity against allogeneic or autologous MSCs [62,[110][111][112][113]. Both Activated T-lymphocytes and Blymphocytes are well known to release RANKL, which boosts osteoclast differentiation from their progenitors and subsequently provoke the bone lysis [94,114]. Totally, although critical at the early phase of bone healing, excess activation of immune cells has a strong link to defective bone formation.…”