Interleukin-33, a Target of Parathyroid Hormone and Oncostatin M, Increases Osteoblastic Matrix Mineral Deposition and Inhibits Osteoclast Formation in Vitro

Abstract

IL-33 is an important inflammatory mediator in allergy, asthma, and joint inflammation, acting via its receptor, ST2L, to elicit Th₂ cell cytokine secretion. IL-33 is related to IL-1 and IL-18, which both influence bone metabolism, IL-18 in particular inhibiting osteoclast formation and contributing to PTH bone anabolic actions. We found IL-33 immunostaining in osteoblasts in mouse bone and IL-33 mRNA expression in cultured calvarial osteoblasts, which was elevated by treatment with the bone anabolic factors oncostatin M and PTH. IL-33 treatment strongly inhibited osteoclast formation in bone marrow and spleen cell cultures but had no effect on osteoclast formation in receptor activator of nuclear factor-κB ligand/macrophage colony-stimulating factor-treated bone marrow macrophage (BMM) or RAW264.7 cultures, suggesting a lack of direct action on immature osteoclast progenitors. However, osteoclast formation from BMM was inhibited by IL-33 in the presence of osteoblasts, T cells, or mature macrophages, suggesting these cell types may mediate some actions of IL-33. In bone marrow cultures, IL-33 induced mRNA expression of granulocyte macrophage colony-stimulating factor, IL-4, IL-13, and IL-10; osteoclast inhibitory actions of IL-33 were rescued only by combined antibody ablation of these factors. In contrast to osteoclasts, IL-33 promoted matrix mineral deposition by long-term ascorbate treated primary osteoblasts and reduced sclerostin mRNA levels in such cultures after 6 and 24 h of treatment; sclerostin mRNA was also suppressed in IL-33-treated calvarial organ cultures. In summary, IL-33 stimulates osteoblastic function in vitro but inhibits osteoclast formation through at least three separate mechanisms. Autocrine and paracrine actions of osteoblast IL-33 may thus influence bone metabolism.

Osteoimmunology: oncostatin M as a pleiotropic regulator of bone formation and resorption in health and disease

“…25 Furthermore, it should be noted that all bone formation depends to some degree on the recruitment of new, primitive osteoblast progenitors. Indeed, OSM shares a number of direct gene targets with PTH in osteoblasts; these include RANKL, 48 IL-33 49 and the transcription factor Zfp467, a factor that regulates osteoblast/adipocyte commitment. 50 This is consistent with the similarity of OSM and PTH effects on bone even though their physiological roles otherwise seem to be quite different.…”

Severe Neutrophil-Dominated Inflammation and Enhanced Myelopoiesis in IL-33–Overexpressing CMV/IL33 Mice

“…In the mouse, an excess of IL-33 activity, caused by systemic or local injection of the recombinant protein (8,(14)(15)(16)(17)(18)(19)(20)(21) by ubiquitous or tissue-specific transgenic overexpression (22,23), or by increased release of the endogenous protein because of removal of its nuclear localization domain (24), was linked to enhanced eosinophil accumulation, eosinophilic organ infiltration, inflammation (8,14,18,(22)(23)(24), basophil expansion (15), or recruitment and activation of neutrophils (16,17,(19)(20)(21). The addition of recombinant IL-33 to cultured mouse bone marrow (BM) cells in different experimental settings promoted cell viability, proliferation, production of myeloid growth factors, and/or modulated cell differentiation (14,15,(25)(26)(27)(28)(29). Furthermore, ST2 expression was described on human and mouse hematopoietic precursor cells, suggesting that IL-33 might exert direct effects on hematopoietic progenitors (30,31).…”

Inhibition of osteoclast differentiation by the interleukin (IL)-1 family cytokine IL-33

“…Another twist to this interesting story is that the effect of IL-33 on bone marrow macrophage precursors to limit commitment to the osteoclast lineage is probably indirect, and mediated by the production of a combination of anti-osteoclastogenic factors such as GM-CSF, IL-4, IL-13 and IL-10, which together optimally inhibit osteoclast differentiation (6). While production of such factors has been observed in cultures of purified mouse CD11b + bone marrow cells, and thus in absence of bone marrow stromal cells (1;2), a recent study suggests that it requires the presence of cell types other than the osteoclast precursors themselves, including, for instance, mature macrophages, T cells or osteoblasts (6) (Fig.…”

“…While production of such factors has been observed in cultures of purified mouse CD11b + bone marrow cells, and thus in absence of bone marrow stromal cells (1;2), a recent study suggests that it requires the presence of cell types other than the osteoclast precursors themselves, including, for instance, mature macrophages, T cells or osteoblasts (6) (Fig. 1).…”