The Runx2-SMOC axis in skeletal development: Expanding roles of Smoc1 and Smoc2 in development and disease

BACKGROUND: Secreted modular calcium-binding proteins (SMOCs), including SMOC1 and SMOC2, are secreted protein acidic and rich in cysteine family matricellular proteins that regulate cell-matrix interactions and growth factor signaling across development and disease. Recent studies positioned SMOC1 and SMOC2 as direct downstream targets of Runt-related transcription factor 2 (Runx2), the master transcription factor for osteoblast differentiation, and revealed dose-dependent modulation of bone morphogenetic protein 2 (BMP2) signaling by SMOC2. HIGHLIGHT: SMOC1/2 exhibit distinct yet complementary roles in skeletal morphogenesis, extracellular matrix assembly, and mineralization. At lower concentrations, SMOC2 enhances BMP2 signaling, whereas at higher concentrations, it inhibits receptor engagement, explaining context-dependent effects on osteogenesis. Genetic evidence from mouse models and human variants (e.g., SMOC2 Leu359Arg) links disrupted SMOC-ECM interactions to growth-plate defects, delayed ossification, and craniofacial phenotypes. Beyond the skeleton, SMOC proteins participate in angiogenesis, ocular development, kidney and testis biology, and platelet thrombin responses. CONCLUSION: The Runx2-SMOC axis provides a mechanistic bridge between transcriptional programs and matricellular control of BMP2 signaling and ECM dynamics. Clarifying isoform-specific functions and ECM anchoring mechanisms will inform therapeutic strategies for skeletal disorders and broader pathologies in which SMOC proteins are implicated.