Molecular events in cartilage formation and remodeling
- Dick Heinegård1
© 2001 BioMed Central Ltd 2001
Received: 15 January 2001
Published: 26 January 2001
Cartilage extracellular matrix contains a major component of highly anionic proteoglycan contributing fixed charges creating and osmotic environment and a swelling pressure important for resisting pressure load. Another key element is a network of fibers with collagen 2 as the major constituent providing tensile properties and an ability to take up load.
In forming the cartilage matrix the cells produce the macromolecules that constitute the building blocks. These are assembled into the structures of the tissue outside of the cells in a number of specific interactions. An example is the fiber network where collagen molecules form fibrils by interactions where a variety of matrix molecules act as catalysts/chaperons or inhibitors.
Examples of molecules interacting with collagen are particularly found among the leucine rich repeat proteins (LRRP). These include decorin, fibromodulin, lumican and biglycan all with known capacity to bind collagens and influence fibrillogenesis in vitro. This binding occurs via the LRR-domain. Furthermore, the molecules have an additional functional domain, that in the case of decorin carries dermatan sulfate chains capable of interacting with other constituents in the matrix including other collagen fibers thereby crossbridging and creating a fibrillar network covering large parts of the tissue.
In the case of decorin, lumican and fibromodulin, mice with inactivated genes show alterations in collagen fibril assembly indicative of roles at different stages of the process. PRELP binds collagen via its repeat domain and heparan sulfate via a characteristic N-terminal extension. This includes binding heparan sulfate at the cell surface. Chondroadherin binds cells via their a2b1 integrin. The molecule can actually be isolated from cartilage bound to collagen 2 molecules after activation of endogenous proteinases.
COMP represents a different class of molecules with five identical subunits held together in their N-terminal end. The C-terminal end of each chain has a structure allowing tight and specific interactions with triple helical collagen. There are four sites along the collagen molecule each with a KD of 10-9. COMP in vitro has a marked effect in catalyzing the correct assembly of collagen fibers, while not binding to the completed fiber. Thus, the molecule act as a chaperon.
Interestingly COMP is upregulated in early phases of osteoarthritis, where a repair attempt of the damaged tissue is likely to be a component. The molecule or fragments thereof released to synovial fluid and blood, actually serves as an indicator of processes in the cartilage leading to its destruction.
In processes in cartilage remodeling, many of the constituents in the matrix are degraded and lost to surrounding body fluids. This degradation is likely to be a response to remodeling following material fatigue, altered load or growth. It may also occur as part of a pathological process. It is likely that it is coupled to attempts at repair laying down new matrix constituents to produce an adequately functioning matrix. In disease it is apparent that the imbalance between breakdown and adequate repair leads to progressive changes in cartilage composition characteristic for the various stages of the disease.