The SIK2/SIK3 inhibitor GLPG3970 increases bone formation and trabecular bone mass in hypogonadal female mice and rats
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PROVIDER: PRJNA1206073 | ENA |
REPOSITORIES: ENA
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Project description:Currently, there are no orally available bone anabolic therapies to treat osteoporosis. Intermittent parathyroid hormone injections stimulate bone formation through a signaling pathway that inhibits the actions of salt inducible kinase (SIK) isoforms 2 and 3. Therefore, direct small molecule SIK2/SIK3 inhibitors represent a promising treatment strategy to mimic PTH actions. Here we tested GLPG3970, a potent and selective SIK2/SIK3 inhibitor developed for clinical use in inflammatory diseases, in rodent models of post-menopausal osteoporosis. In bone cells, GLPG3970 reduces phosphorylation levels of SIK substrates and regulates gene expression patterns, as assessed by RNA-sequencing, in a PTH-like manner. GLPG3970 was administered to female mice and rats rendered hypogonadal via surgical oophorectomy (OVX) via twice daily oral gavage. In parallel, separate groups of rodents were treated with once daily subcutaneous PTH injections. Skeletal endpoints, serum bone turnover markers, micro-CT, histomorphometry, and mechanical testing, were assessed after study termination. In both OVX-operated mice and rats, GLPG3970 treatment increased markers of bone formation and cancellous bone mass, and increased rat vertebral body bone strength. These results provide strong justification for further development of orally available SIK2/SIK3 inhibitors to treat post-menopausal osteoporosis.
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Project description:Germline and osteoblast-directed deletion of G protein-gated inwardly rectifying K+ channel 3 (Girk3) was recently shown to increase bone mass after 18 weeks of age in male mice. Here, we show that germline Girk3 deletion also increases trabecular and cortical bone mass and increases the mechanical strength of the femur in female mice after 18 weeks of age. Unlike male mice, however, osteoblast-directed Girk3 deletion using 2.3kb-Col1a1-Cre does not increase bone mass in adult female mice. To discover mechanisms underlying high bone mass in female Girk3-/- mice, bulk RNA-sequencing was performed on 2-day-old calvarial bone, revealing lower expression of proinflammatory cytokines such as IL-1β and IL-6 in Girk3-/- mice. Accordingly, cytokines and chemokines are largely suppressed in the circulation of adult Girk3-/- mice compared to WT littermates. The cytokines GM-CSF, IL-1β, IL-2, and IL-9 are reduced in the serum of both male and female Girk3-/- mice, while eotaxin, IFNg, and MIP-1a are sexually dimorphic. Histomorphometry reveals that osteoclast activity is modestly reduced in Girk3-/- bone, which is supported by in vitro osteoclast resorption assays. However, deletion of Girk3 in myeloid-lineage cells with LysM-Cre is not sufficient to recapitulate high bone mass in either male or female mice. Moreover, female Girk3-/- mice are not protected from ovariectomy-induced bone loss. Finally, unbiased screening of monocyte populations in the bone marrow via cytometry by time-of-flight revealed no differences in immune cell abundances due to global Girk3 deletion. Taken together, while Girk3 regulates inflammatory cytokine expression in the bone and serum, deletion of Girk3 in myeloid-lineage cells does not affect bone mass.
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Project description:Osteoporosis and other metabolic bone diseases are prevalent in the aging population. While bone has the capacity to regenerate throughout life, bone formation rates decline with age and contribute to reduced bone density and strength. Identifying mechanisms and pathways that increase bone accrual in adults could prevent fractures and accelerate healing. G protein-gated inwardly rectifying K+ (GIRK) channels are key effectors of G protein-coupled receptor signaling. Girk3 was recently shown to regulate endochondral ossification. Here, we demonstrate that deletion of Girk3 increases bone mass after 18 weeks of age. Male 24-week-old Girk3-/- mice have greater trabecular bone mineral density and bone volume fraction than WT mice. Osteoblast activity is moderately increased in 24-week-old Girk3-/- mice compared to WT mice. In vitro, both calvarial osteoblasts and bone marrow stromal cells from Girk3-/- mice are more osteogenic than WT cells and have altered expression of genes that regulate the wingless-type MMTV integration site (Wnt) family. Wnt inhibition via Dickkopf-1 (Dkk1) or β-catenin inhibition via XAV939 prevents the enhanced mineralization, but not proliferation, in Girk3-/- BMSCs and slows these processes in WT cells. Finally, selective ablation of Girk3 from cells expressing Cre from the 2.3kb-Col1a1 promoter, including osteoblasts and osteocytes, is sufficient to increase bone mass and bone strength in male mice at 24 weeks of age. Taken together, these data demonstrate that Girk3 regulates progenitor cell proliferation, osteoblast differentiation, and bone mass accrual in adult male mice.
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