Osteoimmunology and the influence of pro-inflammatory cytokines on osteoclasts

Abstract

Bone and immune system are functionally interconnected. Immune and bone cells derive from same progenitors in the bone marrow, they share a common microenvironment and are being influenced by similar mediators. The evidence on increased bone resorption associated with inappropriate activation of T cells such as during inflammation, is well established. However, the molecular mechanisms beyond this clinical observation have begun to be intensively studied with the advancement of osteoimmunology. Now days, we have firm evidence on the influence of numerous proinflammatory cytokines on bone cells, with the majority of data focused on osteoclasts, the bone resorbing cells. It has been shown that some proinflammatory cytokines could possess osteoclastogenic and/or anti-osteoclastogenic properties and can target osteoclasts directly or via receptor activator of nuclear factor kappaB (RANK)/RANK ligand(RANKL)/osteoprotegerin (OPG) system. Several studies have reported opposing data regarding (anti)osteoclastogenic properties of these cytokines. Therefore, the first part of this review is summarizing current evidence on the influence of pro-inflammatory cytokines on osteoclasts and thus on bone resorption. In the second part, the evidence on the role of pro-inflammatory cytokines in osteoporosis and osteoarthritis is reviewed to show that unravelling the mechanisms beyond such complex bone diseases, is almost impossible without considering skeletal and immune systems as an indivisible integrated system.

Figure 1.

Different influences of pro-inflammatory cytokines on osteoclasts. IL - interleukin; TNF- tumor necrosis factor; IFN - interferon; RANK - receptor activator of nuclear factor κB; RANKL - RANK ligand; OPG - osteoprotegerin; TRAP - tartrate-resistant acid phosphatase; OSCAR - osteoclast associated immunoreceptor.

Figure 2.

Schematic representation of correlations between pro-inflammatory cytokines, osteoclasts-specific genes, bone mineral density and levels of bone turnover markers in osteoporosis and osteoarthritis, according to results of Zupan et al. (146). (−) - denotes negative correlation; (+) - denotes positive correlation; BMD - bone mineral density; RANK/RANKL/OPG - the most significant correlations of pro-inflammatory cytokines with RANK, RANKL and OPG genes are shown; sCathepsin K - cathepsin K serum levels; sOPG - OPG serum levels; sRANKL - RANKL serum levels; OSCAR - osteoclast-associated immunoglobulin-like receptor; CALCR - calcitonin receptor; TRAP - tartrate-resistant acid phosphatase.