The Treadment Of Osteoarthritis

A wide variety of treatments are available for patients with osteoarthritis. Although guidelines for the management of osteoarthritis have been published, rational therapy for individual patients remains difficult because of our relative lack of understanding of the disease process and its outcome.

It is important to let patients know that a diagnosis of osteoarthritis does not necessarily imply progressive disability and declining mobility. In the treatment of osteoarthritis, the goals of therapy include:

• symptom relief
• maintaining and improving optimal and handicap
• minimizing the risk of progression
• facilitating joint healing
• improving the quality of life, and
• helping avoid drug toxicity

The treatment of osteoarthritis should be based on the severity of joint involvement and a full assessment of the patient to determine if local anatomic abnormalities, joint complications, or psychosocial factors contribute to pain and disability. A pyramidal approach may be  used to match the severity of the disease to appropriate nonpharmacologic, pharmacologic, and surgical therapies.

Pathophysiology Of Osteoarthritis

Our understanding of the pathogenesis of osteoarthritis has evolved considerably over the past decade. We now know that osteoarthritis is a dynamic disease process characterized by a disruption in the normal balance between degradation and repair in articular cartilage and subchondral bone. This leads to an abrasion of the articular cartilage on weight-bearing surfaces and the formation of new bone at the edges of the joint. Ultimately, the result is a deterioration of joint funtion.

Many investigators believe that osteoarthritis is initiated by mechanical stress to the joint that alters chondrocyte metabolism. This results in an increased production of degradative enzymes. Cytokines, such as IL-1 and TNF-a, and a variety of growth factors. An imbalance is created between the production of degradative enzymes and the TIMPs that inhibit them. This eventually leads to degradation of the extracellular matrix.

In addition to this degradative process, an ongoing repair process likes place in osteoarthritis characterized by increased synthesis of collagen and proteoglycan. The collagen produced is abnormal, however, and an immature form of aggrecan is synthesized.

It is interesting to note that the structure of aggrecan molecules in the extracellular matrix changes with aging. These chantes include a decrease in the length of chondroitin sulfate chains and an increase in the number and length of keratan sulfate chains. These changes many reflect alterations inthe synthesis of collagen and aggrecan or the cumulative effects of degradative enzymes on the matrix structure.

Similar changes in the composition of aggrecan have been noted in patients with osteoarthritis. Although new proteoglycan continues to be synthesized, even in advanced osteoarthritis, the form of aggrecan produced in an immature, fetal form. This suggests that the chondrocytes revert back to an immature pattern of synthesis.

Summary Points

• Osteoarthritis is characterized by degenerative changes in articular cartilage and by an ongoing repair process.
• Chondrocytes are articular cartilage cells which produce and maintain the extracellular matrix. They occupy only about 1% to 2% of the articular cartilage volume.
• The three primary constituents of the extracellular matrix are water, proteoglycans and collagen.
• Chondrocytes synthesize metalloproteinases and other proteases that can degrade the matrix proteins. These are held in check by inhibitors, such as TIMP and PAI-1.
• Interleukin-1 (IL-1) plays an important role in the stimulation of cartilage degradation. Tumor necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6) appear to act synergistically with IL-1 to promote matrix breakdown.
• Insulin-like growth factor-1 (IGF-1) and transforming growth factor-b (TGF-b) are synthesized by chondrocytes and stimulate chondrocytes to synthesize proteoglycans. They play an important role in the matrix repair process.

The Breakdown and Repair of Articular Cartilage

The structure of the extracellular matrix plays a critical role in the function of articular cartilage. In normal joints, this matrix is constantly being degraded and repaired by chondrocytes. Since matrix synthesis and matrix degradation occur at equal rates, the two processes are normally kept in balance. Both the repair and breakdown processes are controlled by extracellular growth factors and cytokines. A disturbance or alteration in these chemical messengers can initiate disease.

In normal articular cartilage, the turnover rate of extracellular matrix components is slow and the capacity for repair is limited. Collagen turnover is particularly slow. Proteoglycans are more susceptible to enzymatic breakdown and are continually being resynthesized, however.

Insulin-like growth factor-I (TGF-I) and transforming growth factor-b (TGF-b) are synthesized by chondrocytes and stored in the extracellular matrix. When activated, they stimulate chondrocytes to synthesize proteoglycans. IGI-I and TGF-b regulate matrix metabolism in normal cartilage and may play a role in matrix repair in patients with osteoarthritis.

The chondrocytes also synthesize a number of enzymes that can degrade the matrix structure. These are released into the extracellular matrix in an inactive form. Among the enzymes that have been identified as playing a major role in the degradation of collagen and aggrecan molecules are metalloproteinases, such as collagenase, stromelysin, and gelatinase; and serine proteases, such as tissue plasminogen activator.

The activation of these degradative enzymes is held in check by inhibitors, such as tissue inhibitor of metalloproteinase (TIMP) and plasminogen activator inhibitor (PA1-I). TIMP  and PA1-I are synthesized by chondrocytes and limit the degradative activity of active metalloproteinases and plasrainogen activator. If TIMP and PA1-I are destroyed or present insufficient quantities, metalloproteinases and plasmin are free to act on matrix components. Normally, there is a balance between these inhibitors and the degradative enzymes they inhibit.

Thee cytokine interleukin-1 (IL-1) plays an importane role in the stimulation of cartilage degradation. Il-1, which is produced by chondrocytes and other cells in the joint, stimulates the synthesis of degradative enzymes and inhibits the production of proteoglycan. IL-1 may also inhibit the synthesis of TIMP.

Other cytokines that appear to act synergistically with IL-1 to promote matrix breakdown are tumor necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6). All of these cytokines are routinely found in inflamed joints.