{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMSX2 is a homeobox transcription factor that plays a critical role in craniofacial and skeletal development. Mutations or altered dosage of MSX2 have been implicated in nonsyndromic cleft lip and palate and in craniosynostosis, where gain‐of‐function mutations lead to premature suture fusion and defects in frontal bone formation. Moreover, genetic variants in MSX2 have been associated with disorders such as ankylosing spondylitis, and studies in dental precursor cells indicate that its role in osteogenesis may be highly context‐dependent."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn diverse mesoderm‐derived tissues, MSX2 also modulates processes of osteogenic differentiation and calcification. In vascular smooth muscle cells, inflammatory cytokines such as TNF‑α and signals from BMP and Notch pathways up‐regulate MSX2, thereby inducing key osteogenic markers like alkaline phosphatase and promoting vascular calcification. Conversely, in ligaments and tendons the transcriptional activity of MSX2, in association with co‐repressors, appears to block osteoblast differentiation to prevent unwanted mineralization and to preserve tissue integrity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the realm of stem cell differentiation and neoplastic progression, MSX2 emerges as a versatile mediator of cellular fate. In human embryonic stem cells, BMP‐induced MSX2 expression drives mesodermal and cardiovascular lineage commitment, while in the developing fetal ovary it may function as a downstream effector of BMP‐mediated apoptosis. Furthermore, accumulation of MSX2 has been shown to repress SOX2 expression, thereby influencing stem cell properties and drug resistance. Aberrant over‐expression of MSX2 is implicated in tumor progression—promoting epithelial–mesenchymal transition and increasing invasive potential in cancers of the breast, pancreas, ovary, and colon—and its expression in nasal inverted papillomas correlates with recurrence and osteolysis. In addition, elevated MSX2 expression has been noted in induced pluripotent stem cell–derived mesenchymal stromal cells, highlighting its role as a marker of a distinct progenitor state."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Alexandre R Vieira, Joseph R Avila, Sandra Daack-Hirsch, et al. 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