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SP0097 Macromolecules with roles in cartilage and bone homeostasis
  1. D Heinegård
  1. Cell and Molecular Biology, Lund University, Lund, Sweden

Abstract

The extracellular matrix of skeletal tissues contains molecules with key roles in tissue homeostasis. Particularly important are those that are part of the collagen network and maintains its integrity. Examples are members of the thrombospondin family, in cartilage particularly COMP, and members of the family of extracellular leucine rich repeat (LRR) proteins.

These proteins have key roles in the assembly of the collagen II fibrillar network and have the capacity to crosslink neighbouring fibrils by containing at least two functional domains, one binding to one fibril and the other binding to another fibril. An example is decorin showing an interaction site of the core proteins on one hand, while another being the dermatan sulfate side chain. Similarly fibromodulin contains structures with potential for interactions with different collagen fibrillar structures.

Current data indicate that an early event in osteoarthritis is the fragmentation of the binding proteins to separate the functional domains. This will result in an inability of the collagen network to prevent swelling of the tissue and maintain functionality.

The alterations elicit a response where molecules that have roles in catalysing collagen fibril assembly are produced. Such regulating proteins include COMP. This modular protein contains five identical subunits held together close to their C-terminus and having a C-terminal end globular domain that promotes tight binding to collagen. COMP appears to bring together the collagen monomers and catalyse the formation of early fibrils in a chaperon like mode. It is also present, apparently crosslinking completed fibrils by simultaneously binding several collagen IX molecules that are covalently bound on the surface of the collagen II/XI fibres.

Other matrix constituents like PRELP and chondroadherin bind to cell surface molecules, apparently involved in signalling to the cells. These two molecules also bind to collagens I and II.

Cell binding proteins have key roles in bone turnover. Examples are osteopontin, a protein binding the αvβ3 as well as the α4β1 integrin. The protein is produced by the osteoblast and binds to the bone mineralized surface. It then appears to have a central role in recruiting and promoting the development of osteoclast precursors to a fully functional cell. Osteopontin is also expressed by a number of cells in the inflammatory system. It is likely that release of osteopontin in joint destruction will influence the inflammatory response.

Other bone proteins with a capacity to bind αvβ3 include BSP and osteoadherin. Their role in bone turnover and interactions with other tissues remains to be elucidated, but available data indicate primary functions in bone formation.

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