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.
2025-09-01 | GSE285777 | GEO
Project description:We previously described the synthesis and characterization of SK-124, a pharmacologic SIK2/SIK3 inhibitor that increases trabecular bone formation in eugonadal mice. However, the efficacy of this agent in osteoporosis mouse models remains unknown. In this study, we investigated the therapeutic potential of SK-124 in a male hypogonadal bone loss model (orchiectomy, ORX) in BALB/c male mice.Bone RNA-sequencing analysis demonstrated novel pathways associated with increased bone formation in response to SK-124 treatment.
2026-03-31 | GSE310090 | GEO
Project description:The orally available SIK2/SIK3 inhibitor SK-124 increases bone mass in hypogonadal male mice
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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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Project description:scRNA for 8wks trabecular bone
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Project description:This SuperSeries is composed of the following subset Series:; GSE12264: Gene Expression Profile of Osteogenic Cells Derived from Human Bone Marrow and Trabecular Bone I; GSE12265: Gene Expression Profile of Osteogenic Cells Derived from Human Bone Marrow and Trabecular Bone II; GSE12266: Gene Expression Profile of Osteogenic Cells Derived from Human Bone Marrow and Trabecular Bone III Experiment Overall Design: Refer to individual Series
2008-10-21 | E-GEOD-12267 | biostudies-arrayexpress
Project description:Type I diabetes (T1D) impairs bone accrual in patients, but the mechanism is unclear. Here in a murine monogenic model for T1D, we demonstrate that diabetes suppresses bone formation resulting in a rapid loss of both cortical and trabecular bone. Single-cell RNA sequencing uncovers metabolic dysregulation in bone marrow osteogenic cells of the diabetic mice. In vivo stable isotope tracing reveals impaired glycolysis in diabetic bone that is highly responsive to insulin stimulation. Remarkably, deletion of the insulin receptor reduces cortical but not trabecular bone. Increasing glucose uptake by overexpressing Glut1 in osteoblasts exacerbates bone defects in T1D mice. Conversely, activation of glycolysis by Pfkfb3 overexpression preserves both trabecular and cortical bone mass in the face of diabetes. The study identifies defective glucose metabolism in osteoblasts as a pathogenic mechanism for osteopenia in T1D, and furthermore implicates boosting osteoblast glycolysis as a potential anabolic therapy.
2023-06-20 | GSE232736 | GEO
Project description:Type I diabetes (T1D) impairs bone accrual in patients, but the mechanism is unclear. Here in a murine monogenic model for T1D, we demonstrate that diabetes suppresses bone formation resulting in a rapid loss of both cortical and trabecular bone. Single-cell RNA sequencing uncovers metabolic dysregulation in bone marrow osteogenic cells of the diabetic mice. In vivo stable isotope tracing reveals impaired glycolysis in diabetic bone that is highly responsive to insulin stimulation. Remarkably, deletion of the insulin receptor reduces cortical but not trabecular bone. Increasing glucose uptake by overexpressing Glut1 in osteoblasts exacerbates bone defects in T1D mice. Conversely, activation of glycolysis by Pfkfb3 overexpression preserves both trabecular and cortical bone mass in the face of diabetes. The study identifies defective glucose metabolism in osteoblasts as a pathogenic mechanism for osteopenia in T1D, and furthermore implicates boosting osteoblast glycolysis as a potential anabolic therapy.
2023-06-20 | GSE232737 | GEO
Project description:High-throughput microRNA sequencing was used to identify microRNAs (miRs) that regulate osteoblast differentiation. We establish that miR-101a, which targets the epigenetic enzyme Ezh2, is up-regulated in differentiated MC3T3 cells and robustly expressed in mouse calvaria. Our previous studies showed that loss of Ezh2 function enhances osteogenesis and bone formation. Thus, we tested the attractive mechanistic model that increased miR-101s expression may suppress Ezh2 to stimulate the osteogenic process. Transient miR-101a over-expression suppresses Ezh2 levels and reduces tri-methylation on lysine 27 of histone 3 (H3K27me3), a heterochromatic mark catalyzed by Ezh2. Importantly, over-expression of miR-101a stimulates osteogenic differentiation of MC3T3 cells as quantified by alizarin red staining. Therefore, we examined skeletal phenotypes of mice transgenic for miR-101a under the control of Col1a1promoer and doxycycline administration. Experimental controls and mir-101 over-expressing mice were exposed to doxycycline during pregnancy and postnatal stages (phenotyping at 8 weeks) to maximize penetrance of skeletal phenotypes. Our analyses revealed that miR-101a over-expressing male mice are bigger as measured by total body weight and exhibit an increase in long bone length. These mice exhibit significant increases in trabecular bone volume fraction, trabecular number, trabecular thickness, as well as a reduction in trabecular spacing based on microCT analysis. Histomorphometric examination established a significant reduction in osteoid volume to bone volume and osteoid surface to bone surface. These findings suggest that the enhancement in trabecular bone may be due to accelerated bone mineralization in miR-101a over-expressing male mice. Remarkably, while female mice exhibit a significant increase in bone length, no significant changes were noted by microCT (trabecular bone parameters) and histomorphometry (osteoid parameters). We conclude that miR-101a upregulation during osteoblast maturation enhances trabecular bone parameters in male mice. Thus, miR-101 and Ezh2 may form part of an intricate epigenetic feed-forward mechanisms to regulate bone formation.
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