A novel stromal cell source of RANKL during sustained osteoclast activation in disuse osteoporosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE289940 | GEO | 2026/01/05
REPOSITORIES: GEO
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Project description:A novel stromal cell source of RANKL during sustained osteoclast activation in disuse osteoporosis
| PRJNA1225604 | ENA
Project description:Osteoclast over-activation leads to bone loss and chloride homeostasis is fundamental for osteoclast function. The calcium-activated chloride channel Anoctamin 1 (also known as TMEM16A) is an important chloride channel involved in many physiological processes. However, its role in osteoclasts remains unresolved. Here, we identify the existence of Anoctamin 1 in osteoclasts and show that its expression positively correlates with osteoclast activity. Osteoclast-specific Anoctamin 1 knockout mice exhibit increased bone mass and decreased bone resorption. Mechanistically, Anoctamin 1 deletion increases intracellular Cl- concentration, decreases H+ secretion and reduces bone resorption. Notably, Anoctamin 1 physically interacts with RANK and this interaction is dependent upon Anoctamin 1 channel activity, jointly promoting RANKL-induced downstream signaling pathways. Anoctamin 1 protein levels are substantially increased in osteoporosis patients and this closely correlates with osteoclast activity. Finally, Anoctamin 1 deletion significantly alleviates ovariectomy induced osteoporosis. These results collectively establish Anoctamin 1 as an essential regulator in osteoclast function and suggest a potential therapeutic target for osteoporosis.
2022-05-17 | GSE193800 | GEO
Project description:It has been believed that osteoporosis associated with hyperthyroidism due to elevated thyroxine level. But patients with subclinical hyperthyroidism, decline in the level of thyroid stimulating hormone (TSH) alone, are at equal risk of osteoporosis. Research has shown that there is thyroid-stimulating hormone receptor (TSHR) on the osteoclast, but whether TSH regulates osteoclast directly and its mechanisms are still not be stated clearly. In this study, in combination of in vivo and in vitro, we took the osteoclast precursor cell conditional and systemic knockout TSHR mouse models to study the effects of TSHR knockout on bone metabolism in mice and the changes of osteoclast differentiation and function in vitro. Transcriptomics was used to screen the differential genes and signal pathways, and the in vitro experiments were verified. We found that Tshr flox/ flox Lyz2-Cre (TSHR MKO) mice display decreased femoral biomechanics and bone density, damaged bone microstructure. Serum bone resorption marker CTX-I was significantly increased, accompanied by an increase in the number of osteoclasts in bone sections in TSHR MKO mice. The percentage of CD11b+ in TSHR knockout mice was decreased compared with control littermates. Osteoclasts from Tshr -/- mice had stronger osteoclast differentiation and acid secretion ability. In vitro cell experiments confirmed TSH effecting osteoclast differentiation and function by activation of AMPK signaling pathway. In conclusion, TSH inhibits osteoclast differentiation and bone resorption by activating AMPK signaling pathway, increases bone mass, and has osteoprotective effect. This will provide a reference for the diagnosis and treatment of osteoporosis, especially thyroid function related bone metabolism bnormalities. TSH structural analogues or AMPK activators are expected to provide new ideas for the development of drugs for the prevention and treatment of osteoporosis.
2025-10-20 | GSE216422 | GEO
Project description:It has been believed that osteoporosis associated with hyperthyroidism due to elevated thyroxine level. But patients with subclinical hyperthyroidism, decline in the level of thyroid stimulating hormone (TSH) alone, are at equal risk of osteoporosis. Research has shown that there is thyroid-stimulating hormone receptor (TSHR) on the osteoclast, but whether TSH regulates osteoclast directly and its mechanisms are still not be stated clearly. In this study, in combination of in vivo and in vitro, we took the osteoclast precursor cell conditional and systemic knockout TSHR mouse models to study the effects of TSHR knockout on bone metabolism in mice and the changes of osteoclast differentiation and function in vitro. Transcriptomics was used to screen the differential genes and signal pathways, and the in vitro experiments were verified. We found that Tshr flox/ flox Lyz2-Cre (TSHR MKO) mice display decreased femoral biomechanics and bone density, damaged bone microstructure. Serum bone resorption marker CTX-I was significantly increased, accompanied by an increase in the number of osteoclasts in bone sections in TSHR MKO mice. The percentage of CD11b+ in TSHR knockout mice was decreased compared with control littermates. Osteoclasts from Tshr -/- mice had stronger osteoclast differentiation and acid secretion ability. In vitro cell experiments confirmed TSH effecting osteoclast differentiation and function by activation of AMPK signaling pathway. In conclusion, TSH inhibits osteoclast differentiation and bone resorption by activating AMPK signaling pathway, increases bone mass, and has osteoprotective effect. This will provide a reference for the diagnosis and treatment of osteoporosis, especially thyroid function related bone metabolism bnormalities. TSH structural analogues or AMPK activators are expected to provide new ideas for the development of drugs for the prevention and treatment of osteoporosis.
2025-10-20 | GSE216421 | GEO
Project description:Bone remodeling, crucial for skeletal integrity, involves osteoclasts and osteoblasts. Osteoclastogenesis, regulated by NFATc1, is activated by c-Fos and NF-κB signaling in response to RANKL. Excessive RANKL signaling contributes to bone loss pathology. Here we reveal denatonium as an inhibitor of RANKL-induced osteoclast differentiation through the p65 pathway. RNA-seq identified downregulated osteoclast-related genes. Affinity chromatography pinpointed 35 denatonium-interacting proteins, with PRDX1 showing specificity. PRDX1 deficiency led to osteoporosis with increased osteoclast activity and enhanced RANKL-induced osteoclast formation. Denatonium blocked PRDX1 lysosomal degradation, stabilizing PRDX1. Through transcription factor binding site analysis, p65 emerged as a major target suppressed by the denatonium-PRDX1 interaction. Chromatin immunoprecipitation confirmed that the denatonium-PRDX1 complex inhibited p65 enrichment at promoter regions critical for osteoclast differentiation. In an osteoporosis animal model, denatonium treatment restored bone health. This study uncovers denatonium's novel role in bone formation regulation by selectively targeting PRDX1, suggesting its potential in osteoporosis treatment.
2024-06-30 | GSE248992 | GEO
Project description:Bone remodeling, crucial for skeletal integrity, involves osteoclasts and osteoblasts. Osteoclastogenesis, regulated by NFATc1, is activated by c-Fos and NF-κB signaling in response to RANKL. Excessive RANKL signaling contributes to bone loss pathology. Here we reveal denatonium as an inhibitor of RANKL-induced osteoclast differentiation through the p65 pathway. RNA-seq identified downregulated osteoclast-related genes. Affinity chromatography pinpointed 35 denatonium-interacting proteins, with PRDX1 showing specificity. PRDX1 deficiency led to osteoporosis with increased osteoclast activity and enhanced RANKL-induced osteoclast formation. Denatonium blocked PRDX1 lysosomal degradation, stabilizing PRDX1. Through transcription factor binding site analysis, p65 emerged as a major target suppressed by the denatonium-PRDX1 interaction. Chromatin immunoprecipitation confirmed that the denatonium-PRDX1 complex inhibited p65 enrichment at promoter regions critical for osteoclast differentiation. In an osteoporosis animal model, denatonium treatment restored bone health. This study uncovers denatonium's novel role in bone formation regulation by selectively targeting PRDX1, suggesting its potential in osteoporosis treatment.
2024-06-30 | GSE248993 | GEO
Project description:The development of predictive markers to determine the tipping point prior to the onset of osteoporosis is essential to mitigate further irrevocable deterioration. In order to determine the early warning signs before osteoporosis, we used the dynamic network biomarker (DNB) approach to analyze the time series gene expression data in the zebrafish osteoporosis model and revealed that cyclin-dependent kinase inhibitor 1A (cdkn1a) is one core member of DNB. We demonstrated that cdkn1a negatively regulates osteogenesis, evidenced by the loss-of-function and gain-of-function studies. On one hand, CRISPR/Cas9-mediated cdkn1a knockout in the zebrafish significantly altered skeletal development and increased bone mineralization. On the other hand, inducible cdkn1a expression significantly contributed to the osteoclast differentiation. We also provide mechanistic clues that cdkn1a participates in osteoclast differentiation by regulating its upstream signaling cascades. Our data provided new insights into the dynamic nature of osteoporosis, and identified cdkn1a as the early-warning signals of osteoporosis onset.
2023-01-01 | GSE194301 | GEO
Project description:Osteoporosis is a common systemic skeletal disorder especially in postmenopausal women due to excessive production and activation of osteoclasts. However, current anti-osteoporotic drugs used in clinical practice may cause some side effects. Thus, it is necessary to further explore the potential mechanisms regulating the differentiation of osteoclast and develop novel targets for the treatment of osteoporosis. In our study, we found that VSIG4 exhibited the most significant decline among VSIG family members. Overexpression of VSIG4 significantly inhibited RANKL-induced osteoclastogenesis and bone resorption function. Mechanismly, the western blot and immunofluorescence results also showed that overexpression of VSIG4 attenuated the expression of osteoclast marker genes and the activation of MAPK and NF-κB signaling pathways. We found that overexpression of VSIG4 could suppress the generation of reactive oxygen species (ROS) and activate the expression of Nrf2 and its downstream antioxidant enzymes. ML385, a potent Nrf2 inhibitor, was found to reverse the inhibitory impact of VSIG4 on osteoclast differentiation. Consistently, overexpression of VSIG4 also rescued OVX-induced bone loss and attenuated the activation of osteoclasts in vivo. Taken together, our results indicated that VSIG4 could be an novel target to address postmenopausal osteoporosis by suppressing osteoclast formation via regulation of Nrf 2-mediated ROS generation.
2023-11-17 | GSE247553 | GEO
Project description:Primary osteoporosis, manifesting as decreased bone mass and increased bone fragility, is a “silent disease” that is often ignored until a bone breaks. Accordingly, it is urgent to develop reliable biomarkers and novel therapeutic strategies for osteoporosis treatment. Here, we identified REGγ as a potential biomarker of osteoporotic populations through proteomics analysis. Next, we demonstrated that REGγ deficiency increased osteoclast activity and triggered bone mass loss in REGγ knockout (KO) and bone marrow-derive macrophage (BMM)-conditional REGγ KO mice. However, the osteoclast activity decreased in BMM-conditional REGγ overexpression mice. Mechanistically, we defined that REGγ-20S proteasome directly degraded TRAF6 to inhibit bone absorption in a ubiquitin-independent pathway. More importantly, BMM-conditional Traf6 KO with REGγ KO mice could “rescue” the osteoporosis phenotypes. Based on NIP30 (a REGγ “inhibitor”) dephosphorylation by CKII inhibition activated the ubiquitin-independent degradation of TRAF6, we selected TTP22, an inhibitor of CKII, and defined that TTP22 could alleviate osteoporosis in vitro and in vivo. Overall, our study reveals a unique function of NIP30/REGγ/TRAF6 axis in osteoporosis and provides a potential therapeutic drug TTP22 for osteoporosis.
2024-10-27 | PXD057237 |
Project description:Hibernation is energy saving adaptation involving suppression of activity to survive in highly seasonal environments. Immobility and disuse generate muscle loss in most mammalian species. In contrast to other mammals, bears and ground squirrels demonstrate limited muscle atrophy over the physical inactivity of winter hibernation. This suggests that hibernating mammals have adaptive mechanisms to prevent disuse muscle atrophy. To identify common transcriptional program underlying molecular mechanisms preventing muscle loss, we conducted a large-scale gene expression screening in hind limb muscles comparing hibernating and summer active black bears and arctic ground squirrels by the use of custom 9,600 probe cDNA microarrays. The molecular pathway analysis showed an elevated proportion of overexpressed genes involved in all stages of protein biosynthesis and ribosome biogenesis in muscle of both species during hibernation that implies induction of translation at different hibernation states. The induction of protein biosynthesis likely contributes to attenuation of disuse muscle atrophy through prolonged periods of immobility and starvation. This adaptive mechanism allows hibernating mammals to maintain full musculoskeletal function and preserve mobility during and immediately after hibernation, thus promoting survival. The lack of directional changes in genes of protein catabolic pathways does not support the importance of metabolic suppression for preserving muscle mass during winter. Coordinated reduction of multiply genes involved in oxidation reduction and glucose metabolism detected in both species is consistent with metabolic suppression and lower energy demand in skeletal muscle during inactivity of hibernation. Black bears sampled during winter hibernation were compared with the animals sampled during summer. Muscle tissue were hybridized on a custom 12,800 cDNA probe nylon membrane microarray platform . Six hibernating and six summer active bears were studied in the experiment.
2014-10-16 | E-GEOD-62220 | biostudies-arrayexpress