Abstract / Summary
Abstract Bone marrow stromal cell (BMSC) fate is central to the remodelling imbalance that accompanies osteoporosis, but the upstream regulators linking glucocorticoid signalling to the osteogenic–adipogenic fate balance remain incompletely defined. Here we combine transcriptomic reanalysis, promoter and public regulatory evidence, and receptor-output correlation to characterise the relationship between the glucocorticoid receptor (GR/NR3C1) and SCARA5 in osteoporosis-relevant BMSC fate. In human mesenchymal stromal cells (hMSCs) undergoing osteogenic induction, SCARA5 was among the most strongly regulated transcripts: it fell 7.7-fold (log2FC = −2.94, adjusted P = 4.7e-169) under Pyk2 inhibition and ranked in the top 10 of 15,410 tested genes by adjusted P value, while the canonical osteogenic marker ALPL rose (log2FC = +2.19, adjusted P = 4.6e-185). Because dexamethasone was present in both arms of this dataset and NR3C1 transcript was unchanged (log2FC = −0.13), the dataset identifies SCARA5 as a strongly regulated effector in a glucocorticoid-containing osteogenic context but cannot by itself attribute that regulation to GR. NR3C1 mRNA was not a readout of GR activity: in an independent glucocorticoid-treated primary BMSC dataset, six canonical GR target genes were induced in all four donors while NR3C1 mRNA fell (log2FC = −0.65, adjusted P = 1.6e-21). A candidate glucocorticoid response element is present in the SCARA5 proximal promoter, and public ENCODE GR ChIP-seq nominates the locus as GR-responsive in non-BMSC cell lines; however, GR activation alone did not induce SCARA5 in undifferentiated primary BMSCs. Receptor-output correlation identified ferritin/iron handling as the strongest SCARA5-linked module (mean |r| = 0.909, 8 of 10 genes significant), with FTH1 (r = +0.9985), SLC40A1 (r = +0.9895) and FTL (r = +0.9850) as positive anchors and the osteogenic markers COL1A1 (r = −0.9997) and ALPL (r = −0.9989) inversely correlated. Together these findings position GR–SCARA5 as a context-dependent, receptor-output-coupled axis in osteoporotic marrow remodelling, and define a regulatory nomination whose causal validation requires functional perturbation.