Osteoarthritis results from changes in joint cartilage and its matrix. To label it abnormal we must first understand what we call as normal.
Normal articular cartilage is composed of two major macromolecular species-
- Proteoglycans (PGs), which are responsible for the compressive stiffness of the tissue and its ability to withstand load,
- Collagen, which provides tensile strength and resistance to shear.
Cartilage also contains a family of matrix metalloproteinases (MMPs), including stromelysin, collagenase, and gelatinase, which can degrade all the components of the extracellular matrix at neutral pH.
Each is secreted by the chondrocyte (Cell that forms cartilage) as a latent proenzyme (precursor of enzyme) that must be activated by proteolytic cleavage.. The level of MMP activity in the cartilage at any given time represents the balance between activation of the proenzyme and inhibition of the active enzyme by tissue inhibitors.
The turnover of normal cartilage is effected through a degradative cascade, for which driving force is considered to be interleukin (IL), a cytokine produced by mononuclear cells (including synovial lining cells) and synthesized by chondrocytes.
IL-1 stimulates the synthesis and secretion of the latent MMPs and of tissue plasminogen activator.
Plasminogen, the substrate for the latter enzyme, may be synthesized by the chondrocyte or may enter the cartilage from the synovial fluid.
Both plasminogen and stromelysin may play a role in activation of the latent MMPs. IL-1 also suppresses prostaglandin synthesis by the chondrocyte, a substance required for matrix repair. This in turn leads to inhibition of matrix repair.
The balance of the system lies with at least two inhibitors
- Tissue inhibitor of metalloproteinase (TIMP) and
- Plasminogen activator inhibitor-I (PAI-1)
Both are synthesized by the chondrocyte and limit the degradative activity of MMPs and plasminogen activator, respectively. If TIMP of PAI-1 is destroyed or is present in concentrations that are insufficient relative to those of active enzymes, plasmin and other degrading enzymes are free to act on matrix substrates.
Stromelysin can degrade the protein core of the prostaglandins and activate latent collagenase. Conversion of latent stromelysin to an active, highly destructive protease by plasmin provides a second mechanism for matrix degradation.
Polypeptide mediators, e.g. insulin-like growth factor-1 (IGF-1) and transforming growth factor, stimulate biosynthesis of prostaglandins. They regulate matrix metabolism in normal cartilage and may play a role in matrix repair in OA.
These growth factors modulate catabolic as well as anabolic pathways of chondrocyte metabolism, by down-regulating chondrocyte receptors for IL-1, they may decrease PG degradation.
In addition to its responsiveness to cytokines and a variety of other biologic mediators, chondrocyte metabolism in normal cartilage can be modulated directly by mechanical loading.
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