ArticleStem cell research & therapy2025
PBX1 promotes osteoporosis by upregulating HMGB1 to suppress osteogenic differentiation of bone marrow mesenchymal stem cells.
Article in Stem cell research & therapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundOsteoporosis is a common skeletal disorder characterized by low bone mass and impaired bone formation, driven in part by defective osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs).
methodsTranscriptomic profiling, molecular biology techniques, functional assays, and pharmacological inhibition were used to investigate the regulatory role and downstream effects of candidate genes during BMSC osteogenic differentiation.
resultsTranscriptome-based screening identified Pre-B-cell leukemia homeobox 1 (PBX1) as a candidate gene consistently upregulated in samples with low bone mass. During osteogenic induction, PBX1 expression declined progressively, inversely correlating with classical osteogenic markers. Functional experiments demonstrated that PBX1 knockdown enhanced expression of Runt-related transcription factor 2 (RUNX2), Osterix (OSX), and Osteocalcin (OCN), increased Alkaline phosphatase (ALP) activity, and reduced apoptosis, while PBX1 overexpression exerted the opposite effects. Mechanistically, PBX1 directly bound to the proximal promoter of High mobility group box 1 (HMGB1) and transcriptionally activated its expression. Rescue experiments revealed that overexpression of HMGB1 partially reversed the enhanced osteogenesis caused by PBX1 knockdown, confirming HMGB1 as a downstream effector. Time-course transcriptomic analysis and gene network correlation further linked PBX1 to pathways involving inflammation, cellular aging, and stemness maintenance. Pharmacological inhibition of PBX1 with TCRS-417 resulted in dose-dependent downregulation of both PBX1 and HMGB1, while significantly restoring osteogenic gene expression and mineralization capacity, underscoring its therapeutic potential for promoting bone formation in osteoporotic conditions.
conclusionPBX1 acts as an upstream transcriptional regulator that suppresses osteogenic differentiation in part by activating HMGB1, and pharmacological inhibition of PBX1 restores osteogenic potential.
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