Thrombospondins and novel TSR-containing proteins, R-spondins, regulate bone formation and remodeling

Thrombospondins (TSPs) are a family of five secreted multimeric matricellular proteins that share homology in the type II and III repeats and carboxy-terminal region. Type I repeats, also known as properdin or thrombospondin repeats (TSRs), are found in TSP1/2, but not TSP3-5. A variety of other secreted proteins contain TSRs, including the novel extracellular molecules, R-spondins. TSP family and many TSR-containing proteins, including R-spondins, are highly expressed in skeletal tissues during development and postnatal. TSP2 regulates the osteoblast lineage, influencing bone mass and geometry, as well as response to fracture healing, ovariectomy, and mechanical loading. Compound knockout mice of TSPs have revealed important mechanistic insights. TSP1/2 knockout mice have craniofacial dysmorphism, and TSP1/3/5 compound knockout mice display growth plate abnormalities. R-spondins promote osteoblast differentiation and R-spondin-2 deficiency results in skeletal developmental defects. Overall, TSP and other TSR molecules influence multiple aspects of bone development and remodeling.