The biology of small leucine-rich proteoglycans in bone pathophysiology

Abstract

The class of small leucine-rich proteoglycans (SLRPs) is a family of homologous proteoglycans harboring relatively small (36-42 kDa) protein cores compared with the larger cartilage and mesenchymal proteoglycans. SLRPs have been localized to most skeletal regions, with specific roles designated during all phases of bone formation, including periods relating to cell proliferation, organic matrix deposition, remodeling, and mineral deposition. This is mediated by key signaling pathways regulating the osteogenic program, including the activities of TGF-β, bone morphogenetic protein, Wnt, and NF-κB, which influence both the number of available osteogenic precursors and their subsequent development, differentiation, and function. On the other hand, SLRP depletion is correlated with degenerative diseases such as osteoporosis and ectopic bone formation. This minireview will focus on the SLRP roles in bone physiology and pathology.

FIGURE 1.

Schematic representation of the roles of SLRPs and their specific signaling pathways in osteogenesis and remodeling. A, SLRPs have specific roles during all phases of bone formation, including periods relating to cell proliferation, organic matrix deposition, remodeling, and mineral deposition. B, binding of TGF-β to SLRPs (decorin and lumican) regulates its downstream Smad2/3 signaling by facilitating or inhibiting ligand presentation to respective receptors to control bone formation. C, biglycan stimulates ERK phosphorylation and signal transduction through the transcription factor Runx2 to promote osteoblast differentiation. D, biglycan sustains the binding of BMP2/ALK6 to enhance Smad1/5/8 phosphorylation to facilitate downstream signaling relevant to osteogenesis. E, biglycan promotes Wnt3a binding to the LRP6 coreceptor subunit (which engages the Frizzled receptor for complete Wnt-mediated signaling), thereby activating β-catenin signaling to promote bone growth. TCF, T cell factor.