Bone matrix proteins: regulators of skeletal remodeling and repair

The bone extracellular matrix (ECM) is no longer viewed as a passive scaffold, but as an instructive niche that actively governs skeletal development, homeostasis, and regeneration. It functions beyond mechanical and structural support, serving as a solid-phase signaling hub that sequesters and releases morphogens such as TGF-β, BMPs, and Wnt ligands, thereby coupling matrix remodeling to mesenchymal stromal cell differentiation, osteogenic progenitor expansion, and late-stage mineralization.

In this review, we summarize the current understanding of how collagens, glycoproteins, and proteoglycans assemble into a dynamic, viscoelastic composite with multiscale porosity and pronounced stiffness gradients that shape skeletal tissue. We discuss how these physical and biochemical properties are continuously shaped by ECM-modifying enzymes, including lysyl oxidases (LOX/LOXLs), transglutaminases, MMPs, and ADAMTS proteases, and how the ECM is further regulated by non-enzymatic glycation in aging and diabetes. We also examine the role of osteocytes as orchestrators of ECM turnover, emphasizing perilacunar and canalicular remodeling and the PHEX/MEPE/ASARM axis in coordinating mineralization and phosphate homeostasis. In the context of regeneration, we summarize emerging roles for matricellular proteins such as periostin and tenascin-C in coordinating regenerative programs. The bone ECM is a dynamically regulated structure whose biochemical and physical properties are continuously modified by enzymatic and non-enzymatic processes. Osteocytes play a central role in orchestrating ECM turnover and mineralization. Matricellular proteins, particularly osteolectin (OLN), exemplify how matrix-associated ligands can activate Wnt signaling through integrin α₁β₁. We argue that systematic mining of the bone ECM-secreted proteome will uncover additional cell-type-restricted anabolic cues and therapeutic opportunities for genetic dysplasias, fracture non-unions, osteoporosis, and metabolic bone fragility.