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RNA Sequencing Analysis of Osteoclast Precursor Cells under Dexamethasone Stimulation

ABSTRACT: Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is a refractory joint disease caused by prolonged and excessive use of glucocorticoids (GCs). Excessive osteoclast activation has been implicated in the pathological bone erosion of GIONFH. Our previous study found that dexamethasone (10-8M) stimulation significantly enhances osteoclast formation in vitro. To identify therapeutic targets for GIONFH by characterizing glucocorticoid-driven transcriptional alterations in osteoclastogenesis, we performed RNA sequencing on osteoclast precursor cells (OPCs) under RANKL (25ng/ml) and Dex condition (treated with RANKL (25ng/ml) and Dex(10-8M) ) for 24 hours.

ORGANISM(S): Mus musculus

PROVIDER: GSE298117 | GEO | 2025/05/30

REPOSITORIES: GEO

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Project description:Purpose: Among the diverse cytokines involved in osteoclast differentiation, IL-3 has been shown to inhibit RANKL-induced osteoclastogenesis. However, the mechanism underlying IL-3-mediated inhibition of osteoclast differentiation is not fully understood. In the present study, we demonstrate that IL-3 activation of STAT5 inhibits RANKL-induced osteoclastogenesis through the induction of Id genes. Methods: To investigate the effect of STAT5 on osteoclast differentiation and IL-3-mediated inhibition of osteoclast differentiation, bone marrow derived macrophages isolated from STAT5 wild-type (Stat5fl/fl) or STAT5 cKO (STAT5;MX1-Cre) were differentiated to osteoclast in the presence of M-CSF and RANKL with or without IL-3; and bone marrow derived macrophges from STAT5 wild-type and STAT5 cKO were overexpressed with PMX-FIG (control) or STAT5A1*6 (constitutively active form of STAT5A) and differentiated to osteoclast. To analyze bone phenotype, femurs and tibiae of 16 week-old STAT5 wild-type and STAT5 cKO were subjected to micro CT analysis and histomorphometry, respectively. Results: Overexpression of STAT5 inhibited RANKL-induced osteoclastogenesis. However, RANKL did not regulate either expression or activation of STAT5 during osteoclast differentiation. STAT5 deficiency prevented IL-3-mediated inhibition of osteoclastogenesis, suggesting that STAT5 plays an important role in IL-3-mediated inhibition of osteoclast differentiation. In addition, IL-3-induced STAT5 activation upregulated expression of the Id1 and Id2 genes, which are negative regulators of osteoclastogenesis. Overexpression of ID1 or ID2 in STAT5-deficient cells reversed osteoclast development recovered from IL-3-mediated inhibition. Moreover, micro-computed tomography and histomorphometric analysis revealed that STAT5 conditional knockout mice showed reduced bone mass, with an increased number of osteoclasts. Furthermore, IL-3 inhibited RANKL-induced osteoclast differentiation less effectively in STAT5 conditional knockout mice than in wild-type mice in a RANKL injection model. Conclusion: Taken together, our results suggest that STAT5 is a key transcription factor for IL-3-mediated inhibition of RANKL-induced osteoclastogenesis through Id gene expression. Examination of 4 different combination of osteoclast differentiation condition of bone marrow derived macrophages.

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RNA Sequencing Analysis of Osteoclast Precursor Cells under Dexamethasone Stimulation

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