Cartilage Oligomeric Matrix Protein/Thrombospondin 5 Supports Chondrocyte Attachment through Interaction with Integrins

Abstract

Cartilage oligomeric matrix protein/thrombospondin 5 (COMP/ TSP5) is a major component of the extracellular matrix of the musculoskeletal system. Although COMP/TSP5 abnormalities are associated with several pathological conditions, its normal function remains unclear. This study was undertaken to delineate the function(s) of COMP/TSP5 in cartilage, especially regarding its interaction with chondrocytes. We show that COMP/TSP5 can support chondrocyte attachment and that the RGD sequence in COMP/ TSP5 and the integrin receptors ␣5␤1 and ␣V␤3 on the chondrocytes are involved in mediating this attachment. The interactions of COMP/TSP5 with the integrins are dependent on COMP/TSP5 conformation. Chondrocyte attachment to COMP/TSP5 in the calcium-replete conformation was inhibited by function-blocking integrin ␣5 and ␤1 antibodies, suggesting the involvement of the ␣5␤1 integrin. Under this condition, a function-blocking antibody against ␣V␤3 did not have any effect on cell attachment. On the other hand, chondrocyte attachment to reduced COMP/TSP5 was instead sensitive to ␣V␤3 function-blocking antibodies, suggesting that COMP/TSP5 mediates attachment through chondrocyte ␣V␤3 integrin under this condition. Cell attachment to reduced COMP/TSP5 was not inhibited by ␤1 antibodies. These data indicate that COMP/TSP5 in different conformations can utilize different integrin receptors. These results are the first to demonstrate that COMP/TSP5 can mediate chondrocyte attachment through interactions with integrins. Through these interactions, COMP/ TSP5 may be able to regulate cellular activities and respond to environment in the surrounding cartilage matrix.Cartilage oligomeric matrix protein (COMP), 2 also known as thrombospondin 5 (TSP5), is an abundant extracellular matrix protein that has been shown to exist in tissues of the musculoskeletal system including cartilage, tendon, ligament, and synovium (1-7). Immunohistochemistry studies of COMP/TSP5 distribution in cartilage have revealed specific temporal and spatial patterns, and COMP/TSP5 can be found in cartilage at sites both in proximity to chondrocytes in the pericellular matrix and away from the cells in the territorial and interterritorial matrix (8 -10). In fetal cartilage, COMP/TSP5 exists in the pericellular matrix, especially in the growth cartilage adjacent to the primary ossification center. In adult articular cartilage, COMP/TSP5 is found at higher levels in the interterritorial matrix, with stronger staining in the deeper zone (8 -10).The importance of COMP/TSP5 is suggested by its association with several pathological conditions. Compared with normal cartilage, the levels and patterns of COMP/TSP5 expression were found to change in cartilage of osteoarthritis and rheumatoid arthritis patients, and COMP/TSP5 in serum and synovial fluid has been suggested as a biomarker for these conditions (11-13). The importance of COMP/ TSP5 to cartilage structure and function is further underscored by findings that COMP/TSP5 mutations lead to human skeletal dysplasias, p...

Disruption of Extracellular Matrix Structure May Cause Pseudoachondroplasia Phenotypes in the Absence of Impaired Cartilage Oligomeric Matrix Protein Secretion

“…This observation suggests that different pathways lead to reduced viability, one presumably depending on the unfolded protein response induced by retained proteins (14,16,19), another on extracellular mechanisms, possibly involving altered chondrocyte-matrix interactions, as demonstrated here by impaired cell attachment of primary chondrocytes to mutant COMP variants. It has been shown that chondrocytes bind to COMP through receptors of the integrin family (47) and that integrin-mediated interactions with collagen II are important for chondrocyte survival (48 -50). It is conceivable that either an altered binding of COMP to integrin receptors or the COMP-mediated disruption of the extracellular matrix may induce apoptosis.…”

Suppression of inflammation and structural damage in experimental arthritis through molecular targeted therapy with PPI‐2458

“…COMP is a major component of the extracellular matrix of the musculoskeletal system that mediates chondrocyte attachment through interactions with integrins (28). The amount of COMP present in the serum of animals treated with vehicle or PPI-2458 was measured at the conclusion of the treatment.…”

Skeletal Abnormalities in Mice Lacking Extracellular Matrix Proteins, Thrombospondin-1, Thrombospondin-3, Thrombospondin-5, and Type IX Collagen

“…22 Binding experiments demonstrate that TSP5 interacts with types I, II and IX collagens, MATN3, aggrecan, granulin-epithelin precursor, and integrins. [22][23][24][25][26][27][28] The presence of an ordered intracellular matrix network in pseudoachondroplasia chondrocytes and colocalization of these proteins in the normal ECM suggest that TSP5 has a significant role in the ECM. 20 These observations support a model in which TSP5, type IX collagen, and MATN3 interact and function to establish and maintain the homeostasis of the ECM.…”