Inflammatory osteolysis: a conspiracy against bone

Abstract

There are many causes of inflammatory osteolysis, but regardless of etiology and cellular contexts, the osteoclast is the bone-degrading cell. Thus, the impact of inflammatory cytokines on osteoclast formation and function was among the most important discoveries advancing the treatment of focal osteolysis, leading to development of therapeutic agents that either directly block the bone-resorptive cell or do so indirectly via cytokine arrest. Despite these advances, a substantial number of patients with inflammatory arthritis remain resistant to current therapies, and even effective anti-inflammatory drugs frequently do not repair damaged bone. Thus, insights into events such as those impacted by inflammasomes, which signal through cytokine-dependent and -independent mechanisms, are needed to optimize treatment of inflammatory osteolysis.

Figure 1. Cytokines are key regulators of inflammatory osteolysis.

Despite differences in the pathogenesis of various inflammatory diseases, proximal regulators of osteoclastogenesis are the same, although the “cocktail” of these factors may differ. These factors may act at one or more aspects of the osteoclastogenic pathway from osteoclast generation to activation of resorption. While the homeostatic actions of pro-osteoclast factors (green) are balanced by those that are anti-osteoclast (red), pro-osteoclast factors dominate in inflammatory conditions, thereby increasing osteoclast number and enhancing the cell’s capacity to resorb bone. Some factors, such as IFN-γ, have context-dependent effects on osteoclasts (see text). HSC, hematopoietic stem cell; OC, osteoclast.

Figure 2. The inflammasomes in osteolysis.

Cytokines such as TNF induce the expression of pro–IL-1β, which lacks the signal peptide for secretion. Recognition of damage- or pathogen-associated molecular patterns (DAMPs or PAMPs) by the receptor/sensor component of the inflammasome (e.g., NLRP3, NLRC4), or activating mutations of some of these receptors, leads to the assembly of the inflammasome, a protein complex containing the receptor, apoptosis-associated speck-like protein containing a CARD (ASC) and caspase 1. Once assembled, this active complex cleaves pro–IL-1β into active IL-1β and triggers cascades that lead to PARP1 cleavage into p89 and p24 fragments. In precursors sensing DAMPs or PAMPs, cleaved PARP1 and autocrine effects of IL-1β, acting through IL-1R, promote maturation of osteoclasts into bone-resorbing cells. Secreted IL-1β can also act in a paracrine manner to increase bone resorption by nearby osteoclasts. Dashed arrows indicate multiple steps.