Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE248799 | GEO | 2024/03/07
REPOSITORIES: GEO
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Project description:Osteoarthritis is an aging-related systemic disease involving the crosstalk of multiple organs/tissues in metabolism and inflammation, yet little is known about the contribution of liver and marrow adipose tissue (MAT). Here we show that MAT-derived complement factor D (CFD) and component 3 (C3) derived from steatotic liver coordinately drive excessive alternative complement activation, resulting in cartilage damage in mice during aging and metabolic disorders. Mechanistically, estrogen-related receptor α (ESRRA) transcriptionally upregulates CFD responding to bone marrow adipocytes (BMAds) expansion. Inhibition of ESRRA/CFD signaling in BMAds blocks the chondrocyte senescence and catabolism triggered by C3 that is released from steatotic hepatocyte, interrupting C3-CFD-MAC cascade, thereby suppressing ERK1/2 phosphorylation and mitochondrial dysfunction. Adipocyte-specific ablation or pharmacological inhibition of ESRRA reduces CFD levels particularly in adipocyte-rich bone marrow, attenuating osteoarthritis progression in aged mice. Our findings highlight a key liver-MAT-cartilage axis bridged by C3-CFD-MAC pathway, raising the potential for adipocyte ESRRA-targeting therapies for aging-related metabolic osteoarthritis.
2026-03-23 | GSE301065 | GEO
Project description:Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow
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Project description:The unique properties of the bone marrow allow for migration and proliferation of multipl myeloma (MM) cells, while also providing the perfect environment for development of quiescent, drug-resistant MM cell clones. Bone marrow adipocytes (BMAds), which have recently been identified as important contributors to systemic adipokine levels, bone strength, hematopoiesis, and progression of metastatic and primary bone marrow cancers, such as MM. Recent studies in myeloma suggest that BMAds can be reprogrammed by tumor cells to contribute to myeloma-induced bone disease, and reciprocally, BMAds support MM cells in vitro. Importantly, most data investigating BMAds have been generated using adipocytes derived by differentiating bone marrow-derived mesenchymal stromal cells (MSCs) into adipocytes in vitro using adipogenic media, due to the extreme technical challenges associated with isolating and culturing primary adipocytes. However, if studies could be performed with primary adipocytes, they likely will recapitulate in vivo biology better than MSC-derived adipocyte, as the differentiation process is artificial and differs from in vivo differentiation, and progenitor cell(s) of the primary BMAd may not be the same as the MSCs precursors used for adipogenic differentiation in vitro. Therefore, we developed and refined three methods for culturing primary BMAds (pBMAds): 2D coverslips, 2D transwells, and 3D silk scaffolds, all of which can be cultured alone or with MM cells to investigate bidirectional tumor-host signaling. To develop an in vitro model with a tissue-like structure to mimic the bone marrow microenvironment, we developed the first 3D, tissue engineered model utilizing pBMAds derived from human bone marrow. We found that pBMAds, which are extremely fragile, can be isolated and stably cultured in 2D for 10 days and in 3D for short term (~2 weeks) or long term (1 month) in vitro. To investigate the relationship between pBMAds and myeloma, MM cells can be added to investigate physical relationships through confocal imaging and soluble signaling molecules via mass spectrometry. In sum, we developed three in vitro cell culture systems to study primary bone marrow adipocytes and myeloma cells, which could be adapted to investigate many diseases and biological processes involving the bone marrow, including other bone-homing tumor types.
2023-01-04 | PXD032753 | Pride
Project description:Amidst the obesity epidemic and advancements in satiety-targeting therapies, the transcriptional control of energy metabolism is crucial for managing obesity. The transcription factor Estrogen-related receptor α (ESRRA) regulates genes involved in mitochondrial biogenesis, gluconeogenesis, oxidative phosphorylation, and fatty acid metabolism. Although not essential for basic cellular function, ESRRA is vital for energy supply during physiological and pathological challenges. Studies show Esrra mutant mice have impaired fat metabolism and absorption, with germline Esrra loss conferring resistance to high-fat diet (HFD)-induced obesity. However, these studies often overlook tissue-specific roles. Esrra knockdown in the medial pre-frontal cortex reduces feeding and HFD-induced obesity, indicating possible neurological involvement. Notably, ESRRA is highly expressed in the gastrointestinal (GI) tract, a key player in dietary lipid metabolism and target of weight loss therapies.This study aims to investigate the impact of intestinal ESRRA and determine whether it contributes to resistance to diet-induced obesity.
2024-07-10 | GSE269825 | GEO
Project description:Amidst the obesity epidemic and advancements in satiety-targeting therapies, the transcriptional control of energy metabolism is crucial for managing obesity. The transcription factor Estrogen-related receptor α (ESRRA) regulates genes involved in mitochondrial biogenesis, gluconeogenesis, oxidative phosphorylation, and fatty acid metabolism. Although not essential for basic cellular function, ESRRA is vital for energy supply during physiological and pathological challenges. Studies show Esrra mutant mice have impaired fat metabolism and absorption, with germline Esrra loss conferring resistance to high-fat diet (HFD)-induced obesity. However, these studies often overlook tissue-specific roles. Esrra knockdown in the medial pre-frontal cortex reduces feeding and HFD-induced obesity, indicating possible neurological involvement. Notably, ESRRA is highly expressed in the gastrointestinal (GI) tract, a key player in dietary lipid metabolism and target of weight loss therapies.This study aims to investigate the impact of intestinal ESRRA and determine whether it contributes to resistance to diet-induced obesity.
2024-07-10 | GSE269824 | GEO
Project description:Glucocorticoids, powerful anti-inflammatory and immunosuppressive agents, can decrease bone mass and quality and increase bone marrow adiposity. Here, we show that a small number of bone marrow adipocytes (BMAds) in mice undergo rapid cellular senescence in response to glucocorticoid treatment. The senescent BMAds acquire a senescence-associated secretory phenotype (SASP), which reinforces and spreads senescence in the bone/bone marrow microenvironment in a paracrine manner. Mechanistically, glucocorticoid treatment increases the synthesis of oxylipins such as 15d-PGJ2 in BMAds to positively regulate the activity of PPARγ, which stimulates the expression of key cellular senescence effector genes. PPARγ activation, in turn, promotes oxylipin synthesis in BMAds, forming a positive feedback loop. Inhibition of the initial BMAd senescence by deleting p16INK4a from adipocytes or pharmacological suppression of the SASP efficiently interrupts the secondary spread of senescent cells and alleviates glucocorticoid-induced bone deficits. We identify senescent BMAds as initial mediators for glucocorticoid-induced bone deterioration and reveal a lipid metabolism circuit that robustly triggers the senescence of BMAds.
2023-06-09 | GSE205732 | GEO
Project description:ESRRA (Estrogen-Related Receptor Alpha) is an orphan nuclear receptor that plays a pivotal role in regulating cellular metabolism, mitochondrial biogenesis, and energy homeostasis through gene transcriptional control. It has been implicated in various physiological processes and diseases, including cancer. However, the transcriptional programs it regulates and the underlying molecular mechanisms are yet to be comprehensively understood. Here, we demonstrated that ESRRA serves as a central regulator in orchestrating the transcriptional activation of ERa-occupied super enhancers (ERSEs) and cognate ERa-target genes. Meanwhile, it downregulates the expression of cytosolic RNA sensors RIG1 and MDA5 to inhibit type I interferon (IFN) and type I IFN-stimulated genes (ISGs). In terms of mechanism, ESRRA is recruited to ERSEs together with ERain response to estrogen, and their binding with ESREs are regulated in a mutual-dependent manner. However, ESRRA directly binds to the promoter regions of RIG1 and MDA5 to suppress their expression. Consistent with these findings, pharmacological inhibition of ESRRA with its inverse agonist XCT790 inhibits estrogen/ERa-induced gene transcription, and enhances the type I IFN pathway and antitumor immunity to suppress breast cancer cell growth both in vitro and in vivo. Co-treatment with XCT790 and endocrine therapy drugs including ERa antagonist Tamoxifen or degrader Fulvestrant exhibited synergistic effects. Furthermore, combination treatment with XCT790 and tamoxifen re-sensitized Tamoxifen-resistant (TamR) ERa-positive breast cancer cells to Tamoxifen treatment. In summary, our findings unveiled that ESRRA is a pivotal regulator of ERSEs and estrogen/ERa-target gene activation, as well as the type I IFN signaling pathway, offering a promising therapeutic avenue for treating ERa-positive breast cancer in the clinic.
2026-02-13 | GSE267724 | GEO
Project description:ESRRA (Estrogen-Related Receptor Alpha) is an orphan nuclear receptor that plays a pivotal role in regulating cellular metabolism, mitochondrial biogenesis, and energy homeostasis through gene transcriptional control. It has been implicated in various physiological processes and diseases, including cancer. However, the transcriptional programs it regulates and the underlying molecular mechanisms are yet to be comprehensively understood. Here, we demonstrated that ESRRA serves as a central regulator in orchestrating the transcriptional activation of ERa-occupied super enhancers (ERSEs) and cognate ERa-target genes. Meanwhile, it downregulates the expression of cytosolic RNA sensors RIG1 and MDA5 to inhibit type I interferon (IFN) and type I IFN-stimulated genes (ISGs). In terms of mechanism, ESRRA is recruited to ERSEs together with ERain response to estrogen, and their binding with ESREs are regulated in a mutual-dependent manner. However, ESRRA directly binds to the promoter regions of RIG1 and MDA5 to suppress their expression. Consistent with these findings, pharmacological inhibition of ESRRA with its inverse agonist XCT790 inhibits estrogen/ERa-induced gene transcription, and enhances the type I IFN pathway and antitumor immunity to suppress breast cancer cell growth both in vitro and in vivo. Co-treatment with XCT790 and endocrine therapy drugs including ERa antagonist Tamoxifen or degrader Fulvestrant exhibited synergistic effects. Furthermore, combination treatment with XCT790 and tamoxifen re-sensitized Tamoxifen-resistant (TamR) ERa-positive breast cancer cells to Tamoxifen treatment. In summary, our findings unveiled that ESRRA is a pivotal regulator of ERSEs and estrogen/ERa-target gene activation, as well as the type I IFN signaling pathway, offering a promising therapeutic avenue for treating ERa-positive breast cancer in the clinic.
2026-02-13 | GSE267725 | GEO
Project description:Osteogenesis imperfecta (OI) is a serious genetic bone disorder characterized by congenital low bone mass, deformity and frequent fractures. Type XV OI is a moderate to severe form of skeletal dysplasia caused by WNT1 mutations. In this cohort study from southern China, we summarized the clinical phenotypes of patients with WNT1 mutations and found the proportion of type XV patients was around 10.3% (25 out of 243) with diverse phenotypic spectrums. Functional assays indicated that mutations of WNT1 significantly impaired its secretion and effective activity, leading to moderate to severe clinical manifestations, porous bone structure and enhanced osteoclastic activities. Analysis of proteomic data from human skeleton indicated that the expression of SOST was dramatically reduced in type XV patients. Single-cell transcriptome data generated from human tibia samples revealed aberrant differentiation trajectory of skeletal progenitors and impaired maturation of osteocytes, resulting in excessive CXCL12+ progenitors and abnormal cell populations with adipogenic characteristics. The integration of multi-omics data from human skeleton delineates how WNT1 regulates the differentiation and maturation of skeletal progenitors, which will provide a new direction for the treatment strategy of type XV osteogenesis imperfecta and relative low bone mass diseases such as early onset osteoporosis.
2024-10-17 | PXD050841 | Pride
Project description:Objective: To explore the role of bone marrow adipocytes (BMAds) in osteoarthritis (OA). Methods: Male and female C57BL/6 mice (n=4/group) underwent meniscectomy (MNX) or SHAM surgery. OA was determined using OARSI score and the number of perilipin+ adipocytes was quantified. Mesenchymal Stromal Cells (MSCs) from MNX and SHAM mice were differentiated into osteoblasts and adipocytes. Human adipocytes and MSCs (n=8) were enzymatically isolated from epiphyseal and metaphyseal marrow, and from subcutaneous adipose tissue (SCAT) of hip OA patients. Human OA MSCs were differentiated into osteoblasts and adipocytes (OA-Diff-hAdipo). Gene expression patterns of epiphyseal and metaphyseal BMAds, SCAT adipocytes and OA-Diff-hAdipo were evaluated by RNAseq (n=4). The effect conditioned media from OA epiphyseal bone (n=5) on the alkaline phosphatase (ALP) activity and mineralization kinetics was assessed in vitro. Results: Increase in BMAd density was positively correlated with cartilage degradation in MNX mice. OA modified the differentiation capacity of MSCs, accelerating adipocyte differentiation and failing to produce osteoblasts in both human and mice. Human epiphyseal, metaphyseal and SCAT adipocytes from the same OA patients each displayed a specific transcriptome, suggesting different functions. Enrichment analysis defined metaphyseal OA-BMAds as cells implicated in hematopoietic stem cell differentiation. On the other hand, epiphyseal OA-BMAds were considered as osteogenic cells showing an up-regulation of genes related to bone mineralization and remodeling. Specifically, OA epiphysis-secreted molecules decreased ALP activity and altered in vitro the mineralization process. Conclusion: All these results support the emergence of BMAds as new cell partners in OA, opening new venues for therapeutic approaches.
2025-03-13 | GSE291355 | GEO