IL-23 Inhibits Osteoclastogenesis Indirectly through Lymphocytes and Is Required for the Maintenance of Bone Mass in Mice

Abstract

IL-23 stimulates the differentiation and function of the Th17 subset of CD4+ T cells and plays a critical role in chronic inflammation. The IL-23 receptor-encoding gene is also an inflammatory disease susceptibility gene. IL-23 shares a common subunit with IL-12, a T cell-dependent osteoclast formation inhibitor, and we found that IL-23 also dose-dependently inhibited osteoclastogenesis in a CD4+ T lymphocyte-dependent manner. When sufficiently enriched, γδ T cells also mediated IL-23 inhibition. Like IL-12, IL-23 acted synergistically with IL-18 to block osteoclastogenesis but, unlike IL-12, IL-23 action depended on T cell GM-CSF production. IL-23 did not mediate IL-12 action although IL-12 induced its expression. Male mice lacking IL-23 (IL-23p19−/−) had ∼30% lower bone mineral density and tibial trabecular bone mass (bone volume (BV)/total volume (TV)) than wild-type littermates at 12 wk and 40% lower BV/TV at 26 wk of age; male heterozygotes also had lower bone mass. Female IL-23p19−/− mice also had reduced BV/TV. IL-23p19−/− mice had no detectable osteoclast defect in trabecular bone but IL-23p19−/− had thinner growth plate hypertrophic and primary spongiosa zones (and, in females, less cartilage remnants) compared with wild type. This suggests increased osteoclast action at and below the growth plate, leading to reduced amounts of mature trabecular bone. Thus, IL-23 inhibits osteoclast formation indirectly via T cells in vitro. Under nonpathological conditions (unlike inflammatory conditions), IL-23 favors higher bone mass in long bones by limiting resorption of immature bone forming below the growth plate.

In Situ Analysis of Interleukin–23– and Interleukin‐12–Positive Cells in the Spine of Patients With Ankylosing Spondylitis

“…In the latter model IL-23 was necessary for induction of lung fibrosis by transforming growth factor ␤. There is evidence that IL-23 might have a different effect under inflammatory conditions versus noninflammatory conditions: it can mediate bonedestructive processes (32,33) and is found within inflammatory lesions in the gut mucosa of patients with Crohn's disease (34), but also induces increased bone mass under noninflammatory conditions (35). We and others have hypothesized that new bone formation starts from fibrous tissue and that the development of fibrous tissue is crucial in AS (4,13,14).…”

Effects of inflammatory and anti‐inflammatory cytokines on the bone

“…IFN-c is the leading cytokine expressed by TH1 lymphocytes TH1 cells and has important functions in host defence. Interestingly, also the major differentiation signal for TH1 cells, IL-12 inhibits osteoclastogenesis [46]. The suppressive function of IFN-c on osteoclast differentiation is based on interference with RANKL signalling, where IFN-c constitutes a negative feedback loop for RANKL-mediated osteoclast activation [52].…”

The Role of Jak/STAT Pathways in Osteoclast Differentiation

“…Both inhibitory and stimulatory roles of IL-23 on osteoclastogenesis through T cells were reported. Quinn et al reported that IL-23 inhibited osteoclast formation from mouse spleen cells in CD4 + T-and γδT celldependent mechanism (Quinn et al, 2008). Mice lacking a subunit of IL-23 (IL-23p19 defi ciency) represented reduced bone mass phenotype, supporting the role of IL-23 in limiting bone resorption in resting conditions.…”