Thrombospondin-5 (TSP5) is a large extracellular matrix glycoprotein found in musculoskeletal tissues. TSP5 mutations cause two skeletal dysplasias, pseudoachondroplasia and multiple epiphyseal dysplasia; both show a characteristic growth plate phenotype with retention of TSP5, type IX collagen (Col9), and matrillin-3 in the rough endoplasmic reticulum. Whereas most studies focus on defining the disease process, few functional studies have been performed. TSP5 knockout mice have no obvious skeletal abnormalities, suggesting that TSP5 is not essential in the growth plate and/or that other TSPs may compensate. In contrast, Col9 knockout mice have diminished matrillin-3 levels in the extracellular matrix and earlyonset osteoarthritis. To define the roles of TSP1, TSP3, TSP5, and Col9 in the growth plate, all knockout and combinatorial strains were analyzed using histomorphometric techniques. While significant alterations in growth plate organization were found in certain single knockout mouse strains, skeletal growth was only mildly disturbed. In contrast, dramatic changes in growth plate organization in TSP3/5/Col9 knockout mice resulted in a 20% reduction in limb length, corresponding to similar short stature in humans. These studies show that type IX collagen may regulate growth plate width; TSP3, TSP5, and Col9 appear to contribute to growth plate organization; and TSP1 may help define the Thrombospondin-5 (TSP5), also known as cartilage oligomeric matrix protein, is the fifth member of the TSP gene family that includes trimeric (TSP1 and TSP2) and pentameric (TSP3, TSP4, and TSP5) protein members.
1First identified in cartilage and considered to be cartilage specific, TSP5 was subsequently found in other musculoskeletal tissues and is used as a marker for osteoarthritis and joint injury.2-9 TSP5 has been intensely studied, because mutations in this gene were shown to cause pseudoachondroplasia and multiple epiphyseal dysplasia (MED/EDM1). 10 -17 Mutations result in a dominantnegative effect on TSP5 causing massive retention of mutant TSP5 and other extracellular matrix (ECM) proteins, including types II and IX collagen and matrillin-3 (MATN3), in large rough endoplasmic reticulum cis-ternae. 15,18 -20 Recent studies show that these ECM proteins associate with TSP5 to form a structured intracellular matrix network. 20 Interestingly, mutations in MATN3 (MED/EDM5) and all three type IX collagen (Col9) genes also cause MED phenotypes (MED/EDM2, -3, and -6) that are typically milder than the MED condition caused by TSP5 mutations.
21Different approaches have attempted to define the role of TSP5. Recent work suggests that TSP5 stimulates chondrocyte proliferation through the binding of granulinepithelin precursor, an autocrine growth factor. 22 Binding experiments demonstrate that TSP5 interacts with types I,