Background Local bone destruction in rheumatoid arthritis, psoriasisarthritis or ankylosing spondylitis is a serious health burden and the major cause of disability and severely reduced quality of life in these diseases. This damage to the bony structures is exclusively mediated by a special cell type, the osteoclast (OC).
Objectives It is important to understand factors and pathways regulating the generation of OCs under inflammatory conditions. As PTEN is a lipid phosphatase and one of the main antagonists of the PI3-kinase, we analyzed the impact of the PI3-Kinase/PTEN axis on OC generation and bone biology in an animal model of inflammatory bone loss.
Methods We induced osteoclastogenesis in wt and PTEN deficient bone marrow cells and measured the generation of OCs, their resorptive capacity and induction of OC differentiation markers in vitro. Moreover, we analyzed mice with a monocyte/macrophage-specific deletion of PTEN (myeloid specific PTEN-/-) by bone histomorphometry and crossed these miceinto hTNFtg animals.
Results We show that myeloid specific PTEN-/- mice have increased osteoclastogenesis in vitro and in vivo when compared to wild-type animals. However, under non-inflammatory conditions, enhanced osteoclastogenesis did not result in systemic bone loss in vivo. However, when we crossed myeloid specific PTEN-/- into hTNFtg mice we found significantly decreased grip strength scores in myeloid specific PTEN-/-/hTNFtg mice compared to wt hTNFtg mice. Joint swelling scores, however, were not different between both groups. In line, myeloid specific PTEN-/-/hTNFtg mice displayed enhanced local bone destruction as well as OC formation in the inflamed joints, whereas the extent of synovial inflammation was not different between the groups. Analysis of the synovial membranes of wt and myeloid specific PTEN-/- animals revealed similar relative compositions of the cellular infiltrate including macrophages, which serve as OC precursors. This suggests that increased capacity for osteoclastogenic differentiation rather than enhanced recruitment of precursor cells is responsible for the enhanced local generation of OCs.
Conclusions Taken together, these data demonstrate that sustained PI3-Kinase activity in myeloid cells specifically elevated the osteoclastogenic potential of these cells, leading to enhanced inflammatory local bone destruction. Therefore, targeting the PI3-Kinase pathway therapeutically may be especially useful for the prevention of structural joint damage.
Disclosure of Interest None Declared