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Effect of RANKL inhibition on fibrous dysplasia lesions (human)

ABSTRACT: we investigated mechanisms underlying RANKL inhibition with the monoclonal antibody denosumab on FD tissue, and its likely indirect effects on osteoprogenitors, by evaluating human FD tissue pre and post-treatment and in murine in vivo pre-clinical models.Results from this study demonstrate that, beyond its expected anti-osteoclastic effects, denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation, leading to increased bone formation within lesions

ORGANISM(S): Homo sapiens

PROVIDER: GSE250355 | GEO | 2024/01/15

REPOSITORIES: GEO

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Effect of RANKL inhibition on fibrous dysplasia lesions (mouse)

Project description:we investigated mechanisms underlying RANKL inhibition with the monoclonal antibody denosumab on FD tissue, and its likely indirect effects on osteoprogenitors, by evaluating human FD tissue pre and post-treatment and in murine in vivo pre-clinical models. Results from this study demonstrate that, beyond its expected anti-osteoclastic effects, denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation, leading to increased bone formation within lesions

2024-01-15 | GSE250356 | GEO

Effect of RANKL inhibition on fibrous dysplasia lesions

Project description:Effect of RANKL inhibition on fibrous dysplasia lesions

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Effect of RANKL inhibition on fibrous dysplasia lesions (human)

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Effect of RANKL inhibition on fibrous dysplasia lesions

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-01-15 | GSE250357 | GEO

Transcriptomic signature and pro-osteoclastic secreted factors of abnormal bone marrow stromal cells in fibrous dysplasia (Mouse)

Project description:Fibrous dysplasia (FD) is a mosaic skeletal disorder caused by somatic activating variants in GNAS, encoding for Gαs, which leads to excessive cAMP signaling in bone marrow stromal cells (BMSCs). Despite advancements in our understanding of FD pathophysiology, the effect of Gαs activation in the BMSC transcriptome remains unclear, as well as how this translates into their local influence in the lesional microenvironment. In this study, we analyzed changes induced by Gαs activation in BMSC transcriptome and performed a comprehensive analysis of their production of cytokines and other secreted factors. We performed RNAseq of cultured BMSCs from patients with FD and healthy volunteers, and from an inducible mouse model of FD, and combined their transcriptomic profiles to build a robust FD BMSC genetic signature. Pathways related to Gαs activation, cytokine signaling, and extracellular matrix deposition were identified. In addition, a comprehensive profile of their secreted cytokines and other factors was performed to identify modulation of several key factors we hypothesized to be involved in FD pathogenesis. We also screened circulating cytokines in a collection of plasma samples from patients with FD, finding positive correlations of several cytokines to their disease burden score, as well as to one another and bone turnover markers. Overall, these data support a pro-inflammatory, pro-osteoclastic behavior of BMSCs bearing hyperactive Gαs variants, and point to several cytokines and other secreted factors as possible therapeutic targets and/or circulating biomarkers for FD.

2024-04-29 | GSE261359 | GEO

Transcriptomic signature and pro-osteoclastic secreted factors of abnormal bone marrow stromal cells in fibrous dysplasia (Human)

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RANKL regulates testicular cancer growth and Denosumab has tumor suppressive effects in GCNIS and advanced seminoma

Project description:Testicular germ cells tumors (TGCTs) have a high sensitivity to cisplatin-based chemotherapy and a high cure rate, although with possible serious adverse effects. In the search for tumor suppressive drugs, the RANKL inhibitor Denosumab, used to treat osteoporosis came up as a candidate since RANKL signaling was recently identified in the testis. RANKL signals through the receptor RANK and this signaling is antagonized by the decoy receptor OPG. Here, we demonstrate expression of RANKL, RANK, and OPG in germ cell neoplasia in situ (GCNIS), TGCTs, and TGCT-derived cell lines. RANKL inhibition reduced proliferation of seminoma-derived TCam-2 cells but had no effect on embryonal carcinoma-derived NTera2 cells in vitro. Denosumab did not potentiate the effect of cisplatin treatment in vitro but inhibition of RANKL in vivo resulted in reduced tumor growth in a TCam-2 but not a NTera2 xenograft model. Moreover, Denosumab treatment decreased proliferation in human testicular GCNIS tissue culture in vitro. In TGCT patients, serum RANKL was not linked with tumor burden, relapse, or other prognostic markers. In conclusion, this study shows that the RANKL signaling system is expressed in GCNIS and seminoma where RANKL inhibition suppress tumor growth in vitro and in vivo. Future studies are needed to determine whether RANKL is important for the malignant transformation and the transition from GCNIS to invasive tumors.

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Immune modulation with RANKL-blockade through denosumab treatment in cancer patients

Project description:Denosumab is a fully human monoclonal antibody that binds receptor activator of nuclear factor-κB ligand (RANKL) and is routinely administered to cancer patients to reduce the incidence of new bone metastasis. RANK-RANKL regulates bone turnover by controlling osteoclast recruitment, development, and activity. However, this interaction also can regulate a broad range of immune cells including dendritic cells and medullary thymic epithelial cells (mTECs). Inhibition of the latter results in reduced thymic negative selection of T cells and could enhance the generation of tumor-specific T cells. We examined whether administering denosumab could modify modulate circulating immune cells in cancer patients. Blood was collected from 23 prostate cancer patients and 3 renal cell carcinoma patients, who provided written informed consent, with advanced disease who were receiving denosumab, prior to and during denosumab treatment. Using high-dimensional mass cytometry, we found that denosumab treatment by itself induced modest effects on circulating immune cell frequency and activation. We also found minimal changes in the circulating T cell repertoire and the frequency of new thymic emigrants with denosumab treatment. However, when we stratified patients by whether they were receiving chemotherapy and/or steroids, patients receiving these concomitant treatments showed significantly greater immune modulation, including an increase in the frequency of NK cells early and classical monocytes later. We also saw broad induction of CTLA-4 and TIM3 expression in circulating lymphocytes and some monocyte populations. These findings suggest that denosumab treatment by itself has modest immunomodulatory effects, but when combined with conventional cancer treatment, can lead to the induction of immunologic checkpoints.

2024-04-10 | GSE248774 | GEO

Patient-Derived Organoids Recapitulate Pathological Intrinsic and Phenotypic Features of Fibrous Dysplasia

Project description:Fibrous dysplasia (FD) is a rare bone disorder characterized by the replacement of normal bone with benign fibro-osseous tissue. Developments in our understanding of the pathophysiology and treatment options are impeded by the lack of suitable research models. In this study, we developed an in vitro organotypic model capable of recapitulating key intrinsic and phenotypic properties of FD. Transcriptomic profiling of individual cells isolated from patient lesional tissues revealed extensive intralesional molecular and cellular heterogeneity, indicative of pathogenic fibrotic processes.

2024-04-23 | GSE263294 | GEO

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