Effects of IL-23 and IL-27 on osteoblasts and osteoclasts: inhibitory effects on osteoclast differentiation

Abstract

Interleukin (IL)-23 and IL-27 are IL-6/IL-12 family members that play a role in the regulation of T helper 1 cell differentiation. Cytokines are known to be involved in the bone remodeling process, although the effects of IL-23 and IL-27 have not been clarified. In this study, we examined the possible roles of these cytokines on osteoblast phenotypes and osteoclastogenesis. We found that IL-27 induced signal transducers and activators of transcription 3 activation in osteoblasts. However, neither IL-23 nor IL-27 showed any significant effects on alkaline phosphatase activity, receptor activator of nuclear factor kappaB ligand (RANKL) expression, mRNA expression such as alkaline phosphatase type I procollagen, or the proliferation of osteoblasts. Osteoclastogenesis from bone marrow cells induced by soluble RANKL was partially inhibited by IL-23 and IL-27 with reduced multinucleated cell numbers, but these interleukins did not affect the proliferation of osteoclast progenitor cells. These results indicate that IL-23 and IL-27 could partly modify cell fusion or the survival of multinucleated osteoclasts. On the other hand, partially purified T cells, which are activated by 2 microg/ml anti-CD3 antibody, completely inhibited osteoclastogenesis by M-CSF/RANKL. On using T cells activated with 0.2 microg/ml anti-CD3 antibody, in which osteoclastogenesis was partially inhibited, the interleukins had additive effects for inhibiting osteoclastogenesis. Although the consequences of phosphorylated signals in osteoblasts have not been identified, IL-23 and IL-27, partly and indirectly through activated T cells, inhibited osteoclastogenesis, indicating that these interleukins may protect against bone destructive autoimmune disorders.

IL‐23 promotes osteoclast formation by up‐regulation of receptor activator of NF‐κB (RANK) expression in myeloid precursor cells

“…These results are in contrast to a report of reduced osteoclast formation upon IL-23 treatment of bone marrow macrophages [48]. This may relate to a difference in expression of IL-23 receptor on BMM derived from the ddY mouse strain as the authors were unable to detect the protein by Western blotting.…”

“…However, it is plausible that an increase in the percentage of precursor cells expressing RANK even under conditions of baseline levels of RANKL could result in enhanced osteoclastogenesis. Further in vivo studies are needed to clarify this issue.These results are in contrast to a report of reduced osteoclast formation upon IL-23 treatment of bone marrow macrophages [48]. This may relate to a difference in expression of IL-23 receptor on BMM derived from the ddY mouse strain as the authors were unable to detect the protein by Western blotting.…”

“…IL-27 has been suggested to act directly on BMM and prevent osteoclastic differentiation by activation of STAT1, similar to IFN-g [48]. We have also observed reduced osteoclast formation in the presence of IL-27, particularly when using high concentrations (420 ng/mL), although the differences did not reach significance.…”

“…However, these differences could at least in part also relate to functions of IL-23 that are independent of Th17 development. Myeloid precursors are responsive to IL-23, and BMM have been shown to express both subunits of the receptors for IL-23 and IL-27 [48]. We have therefore investigated whether the IL-6/IL-12 family cytokines IL-23 and IL-27 influence bone resorption by altering myeloid precursor cell differentiation.…”

Cytokine measurements in Brazilian postmenopausal osteoporosis patients reveal high levels of IL-8

“…By contrast, a recent study found that IL-27 could be beneficial by inhibiting osteoclastogenesis [19]. This study corroborates the findings of other ones that consider IL-27 to be an anti-inflammatory factor [20] and a possible positive inflammatory regulator in arthritis [21], multiple sclerosis [22], and even cancer [23].…”