Bone resorption and osteolysis are a prominent feature and a cause of substantial morbidity in several inflammatory diseases, including rheumatoid arthritis (RA), periodontitis, and peri-prosthetic loosening (1
). Osteoclasts are the primary bone-resorbing cells and are essential for bone destruction in these inflammatory diseases. Osteoclasts are multinucleated giant cells that are differentiated from hematopoietic cells of myeloid lineage. RANKL and M-CSF are essential molecules for differentiation of osteoclasts from their precursors, and these osteoclastogenic molecules are abundantly expressed in inflammatory conditions, such as RA and periodontitis (4
). M-CSF binds to the surface receptor c-Fms (also termed colony-stimulating factor 1 receptor), which is responsible for early differentiation of osteoclasts and acts as a potent stimulator of RANK expression (6
). RANKL binds to RANK on the cell surface of osteoclast precursors (OCPs) and induces the full differentiation of osteoclasts and their bone resorbing activity. Osteoprotegerin is another receptor for RANKL and a potent inhibitor of osteoclastogenesis that acts as a decoy receptor for RANKL. Other inflammatory molecules also positively or negatively contribute to bone destruction by regulating the differentiation of osteoclasts. Therefore, the extent of bone destruction is determined by the balance between stimulatory and inhibitory factors of osteoclastogenesis in inflammatory conditions.
In RA, several inflammatory molecules, such as TNF-α, IL-1β, IL-6, IL-17, and PGs play a vital role in osteoclastogenesis and bone resorption. These molecules promote osteoclastogenesis indirectly by increasing expression of RANKL and M-CSF by stromal cells and T cells, and also by acting directly on OCPs to synergize with RANKL in driving osteoclastogenesis (1
). Among these molecules, TNF-α is the most important osteoclastogenic molecule in pathologic conditions, such as RA. TNF-α increases osteoclastogenesis through several different mechanisms (7
). TNF-α increases the pool size of marrow OCPs, enhances the RANKL-induced osteoclastogenic actions, and increases expression of RANKL in synovial cells, T cells, and osteoblast/stromal cells.
IL-1 is a multifunctional cytokine that has predominately proinflammatory properties but can also engage feedback inhibitory mechanisms (e.g., induction of glucocorticoid production) that restrain and balance its proinflammatory function (8
). This cytokine was initially described as an osteoclast-activating factor due to its potent bone-resorbing activity (9
). Like TNF-α, IL-1β also plays an essential role in the pathogenesis of bone destruction in RA. Although IL-1 alone does not induce osteoclastogenesis, it augments RANKL-induced osteoclast differentiation and promotes osteoclast activation and survival (10
). IL-1 also mediates TNF-induced bone resorption (11
). The IL-1 gene family has several members, such as IL-1α, IL-1β, and the IL-1R antagonist (IL-1Ra) (8
). IL-1α and IL-1β are agonists, and IL-1Ra is a specific receptor antagonist. There are two members of the IL-1R gene family. The type I receptor IL-1RI transduces signals, whereas IL-1RII does not transduce signals and instead works as a decoy receptor. IL-1 exerts its biological effects by forming a complex with the IL-1RI and IL-1R accessory protein. IL-1 uses the adaptor molecule MyD88 to activate signaling pathways leading to the activation of NF-κB and MAPKs and downstream transcription factors that drive inflammatory gene expression (12
While inflammatory molecules, such as TLR ligands, drive bone destruction, these molecules also engage potent homeostatic mechanisms to limit damage associated with inflammation, and these mechanisms may limit the extent of bone resorption. Direct stimulation of various TLRs on OCPs inhibits RANKL-induced osteoclastogenesis in mouse cells (13
), and we also found that TLR ligands inhibit human osteoclast differentiation by acting directly on OCPs (17
). Generally, TLR ligands and other inflammatory molecules inhibit osteoclast differentiation at early stages of osteoclastogenesis, such as generation of OCPs, and lose their inhibitory properties at later stages, at which point they augment RANKL-induced osteoclast differentiation. In chronic inflammatory conditions, TLR ligands and other inflammatory molecules predominately work as proosteoclastogenic molecules, despite their direct inhibitory effect on the osteoclastogenesis.
TLRs and IL-1R share a cytosolic domain, termed Toll–IL-1R, and common intracellular signaling molecules, such as MyD88, IL-1R–associated kinase, and TNFR-associated factor 6 (12
), and the known stimulatory effects of IL-1β on the osteoclast differentiation are similar to the effects of TLR ligands. These findings suggest the possibility that IL-1β also may regulate osteoclast differentiation by acting directly on OCPs, similarly to TLR ligands. Because little is known about the direct effect on human osteoclastogenesis by IL-1β, we examined the effects of IL-1β on osteoclastogenesis in primary human peripheral blood monocytes and RA synovial macrophages. We found that IL-1β induces shedding and thereby inactivation of c-Fms that drives RANK expression and makes early human OCPs refractory to RANK stimulation by downregulating expression of RANK, its costimulatory receptor, triggering receptor expressed on myeloid cells 2 (TREM-2), and downstream signaling molecules, such as B cell linker (BLNK). These findings identify a homeostatic function for a predominately inflammatory cytokine and suggest a new mechanism that can restrain osteoclastogenesis in inflammatory settings.