(OR17-05-24) Western Diet Restores Osteocyte Function in IL-10 Knockout Mice: A Sex-dependent Skeletal Response

Objectives: Interleukin (IL)-10, a well-known anti-inflammatory cytokine, is important in the maintenance of skeletal health. In the absence of IL-10 signaling, bone loss occurs and osteocyte-derived fibroblast-like growth factor 23 (FGF23) is elevated. This study investigated the mechanism through which metabolic stress (e.g., western diet [WD]) affects osteocyte function in the absence of IL-10.

Methods: Male or female 8-wk-old IL-10 KO and wild type (WT) mice were assigned to groups in 2 x 2 factorial design: strain (WT or KO) and diet (AIN-93 control [CO] or WD [high in %kcal from fat & sugar]). After 12 wks on diets, bone mineral density (BMD), serum c-terminal FGF (cFGF-23), gene expression (flushed bone & bone marrow), and bone marrow adipocyte tissue (BMAT) were assessed. Data were analyzed using 2-way ANOVA followed by post hoc tests.

Results: BMD was reduced (P < 0.0001) in female and male IL-10 KO mice compared to WT, but the WD unexpectedly, restored BMD in female KO mice. In both sexes, WD also suppressed the increase in serum cFgf-23 (P < 0.01) and bone Fgf23 gene expression (P < 0.01) in KO mice. The expression of Sost, which encodes for the Wnt inhibitory molecule (sclerostin) and regulates bone marrow adipogenesis, was suppressed (P < 0.05) in both sexes of KO mice; however, the WD normalized Sost (P < 0.05) in female mice. Among female KO mice, indicators of osteoblast activity, osteocalcin (Bgalp2) and type 1 collagen (Col1ɑ1), were also suppressed, but the WD restored gene expression to the WT. Regulators of bone mineralization expressed by osteocytes, dentin matrix acidic phosphoprotein 1 (Dmp1) and phosphate-regulating endopeptidase X-Linked (Phex) were also suppressed in the KO mice, but the WD normalized their expression (P < 0.05) in the females. Interestingly, KO male and female mice exhibited almost no BMAT (P < 0.05). The WD increased BMAT in the female KO mice, although not to the level of WTWD, as well as the expression of peroxisome proliferator-activated-γ (Pparγ) (P < 0.01). These WD-induced changes in the bone phenotype, indices of osteoblast activity and mineralization, and BMAT in female KO mice were not observed in males.

Conclusions: Our data indicate that in the absence of IL-10, WD alters osteocyte function coincident with increased BMAT in females, resulting in an improved bone phenotype.

Funding Sources: Oklahoma Agricultural Experiment Section