Abstract
Interleukin-32 gamma (IL-32γ) is a recently discovered cytokine that is elevated in inflamed tissues and contributes to pathogenic features of bone in human inflammatory rheumatic diseases. Nevertheless, the role of IL-32γ and its direct involvement in bone metabolism is unclear. We investigated the molecular mechanism of IL-32γ in bone remodeling and the hypothetical correlation between IL-32γ and disease activity in osteoporosis patients. Transgenic (TG) mice overexpressing human IL-32γ showed reduced bone loss with advancing age, increased bone formation, and high osteogenic capacity of osteoblast compared to wild-type (WT) mice through the upregulation of miR-29a, which caused a reduction of Dickkopf-1 (DKK1) expression. IL-32γ TG mice were protected against ovariectomy (OVX)induced osteoporosis compared with WT mice. Decreased plasma IL-32γ levels were associated with bone mineral density (BMD) in human patients linked to increased DKK1 levels. These results indicate that IL-32γ plays a protective role for bone loss, providing clinical evidence of a negative correlation between IL-32γ and DKK1 as bone metabolic markers.
Highlights
Interleukin-32 (IL-32), originally called natural killer cell transcript 4, is a 27-kDa secretory glycoprotein[13]
We found that IL-32γTG resulted in the prevention of trabecular bone loss with aging and estrogen-deficiency
The induction rate of DKK1 protein levels in serum after OVX operation was lower in serum from IL-32γTG mice than that of WT mice, with a dramatic increase in serum DKK1 in OVX-induced osteoporotic conditions (Fig. 4g), similar to a previous report[30]. These findings suggest that systemic overexpression of IL-32γprotects against OVX-induced bone loss, and that IL-32γis closely related to DKK1 levels
Summary
Interleukin-32 (IL-32), originally called natural killer cell transcript 4, is a 27-kDa secretory glycoprotein[13]. IL-32γstimulates OC formation in vitro in RA20,21,23 and actively enhances OB differentiation in AS22, indicating controversial effects on bone feature. These considerations led us to evaluate whether systemic IL-32γdisplays an altered phenotype of bone metabolism and has the direct ability to promote bone formation under overexpression conditions of the human IL-32γgene transgenic (TG) mice. Osteoporotic patients exhibited lower levels of human IL-32γthan healthy persons did, accompanied with higher Dickkopf-1 (DKK1) levels. These observations indicate systemic IL-32γmay be a bone-anabolic factor that can serve as a biomarker to represent a low risk of osteoporosis progression when coupled with DKK1
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