FOXJ3 drives mesenchymal stem cell osteogenic differentiation via the Wnt/β‑catenin pathway: A novel regulator...

Osteoporosis involves impaired osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). The present study identified the transcription factor forkhead box (FOXJ3) as a novel regulator of this process. During in vitro osteogenic differentiation of BMSCs, FOXJ3 expression progressively increased, and was positively correlated with osteogenic markers Runt‑related transcription factor 2 (RUNX2) and osteocalcin (OCN). Functional studies confirmed the essential role of FOXJ3: Small interfering RNA‑mediated knockdown markedly impaired differentiation, as evidenced by reduced alkaline phosphatase (ALP) activity, diminished mineralized nodule formation, and downregulation of RUNX2 and OCN. Conversely, lentivirus‑induced FOXJ3 overexpression enhanced these osteogenic markers and outcomes. Mechanistically, FOXJ3 knockdown suppressed active β‑catenin expression, indicating Wnt/β‑catenin pathway involvement. Crucially, the Wnt/β‑catenin agonist SB216763 rescued the inhibitory effects of FOXJ3 knockdown on ALP activity and mineralization. Conversely, the pro‑osteogenic effects of FOXJ3 overexpression were abrogated by the Wnt inhibitor XAV939. These findings establish FOXJ3 as a positive regulator of BMSC osteogenic differentiation acting primarily through the Wnt/β‑catenin pathway, presenting a novel potential therapeutic target for osteoporosis.