Serum and Synovium Protease Inhibitor Levels in Primary and Secondary Osteoarthritic Joints

Evaluation of Serum and Synovium Protease Inhibitor Levels in Primary and Secondary Osteoarthritic Joints, and Comparison for Patients Undergoing Joint Replacement

Osteoarthritis (OA) is the irreversible degeneration of articular cartilage and underlying bone. It poses a major healthcare problem as it is the leading cause of joint disease and disability in the United States. It was traditionally thought that OA was a consequence of aging and joint trauma. However, it is now thought that OA is a result of the interplay of multiple genetic, biomechanical, and biochemical factors that disrupt the normal homeostasis of cartilage, bone, and synovium.

OA is classified into two groups, primary and secondary. Primary OA is classically polyarticular and peripheral while secondary OA can commonly be attributed to a specific cause, limited to a singular joint, and a result of trauma. It is known as post-traumatic OA (PTOA). Other causes of secondary OA include congenital disorders, calcium pyrophosphate dehydrate deposition disease, and other diseases. Regardless of classification, genetic variation in the normal metabolism of cartilage and bone is thought to play a role in the progression of OA. Furthermore, the polyarticular presentation of primary idiopathic osteoarthritis suggests that it may have a stronger genetic component as compared to secondary OA, indicating a deviation from normal cartilage and bone homeostasis.

Matrix metalloproteinases (MMP) and their inhibitors take part in the metabolism of cartilage and bone. MMPs are enzymes that catalyze the degradation of elements within joint spaces while their inhibitors cease this activity. Alpha-2-Macroglobulin (A2M) is a naturally-occurring plasma glycoprotein that functions throughout multiple tissues and extracellular spaces as a protease inhibitor but does not normally reach high levels within the intra-articular joint space. A2M is believed to modulate the systemic inflammatory response by its ability to bait, trap, and clear various MMPs and cytokines. Concentrated A2M directly addresses the roles of cytokines and catabolic enzymes known to participate in the development of osteoarthritis. Cytonics has shown that A2M can inhibit cartilage degradation in vitro. As the role of MMPs and protease inhibitors have emerged as key components of OA, the investigation of regulators of MMP has become of interest to elucidate the pathogenesis and possible novel treatments of OA.

This study aims to measure and correlate the levels of alpha-2-Macroglobulin (A2M) in plasma and knee joint OA between primary post-traumatic (PTOA) and secondary osteoarthritis groups.

This is a single institution observational study.

Pre-procedure diagnosis: Based on chart review and consultation with operating surgeon of subjects undergoing total knee arthroplasty, patients will be grouped into primary or secondary (PTOA) osteoarthritis groups. Primary osteoarthritis will be identified through a clinical presentation of generalized osteoarthritis with possible bilateral involvement and no identifiable trauma or overuse to knee joint. Secondary osteoarthritis will be identified by history of overuse or trauma to the afflicted knee and a clinical presentation that in general lacks symmetrical involvement and/or severity, PTOA.

On the date of surgery, both primary and secondary groups will have 2 cc whole blood collected via venipuncture during placement of intravenous access for anesthesia. No additional venipuncture is necessary and this study necessitates no instrumentation/manipulation of patient beyond that of IV access normally obtained preoperatively. Blood will then be placed in refrigerated storage (2-6 C) until analyzed for A2M assay.

On the date of surgery, joint aspirate from both primary and secondary groups will be collected by the operating surgeon during knee arthroplasty. At the time of arthrotomy, joint fluid that is expressed from surgical site will be harvested and placed into an eppendorf tube and placed on ice. The study incurs no further risk to the patient and no further instrumentation/manipulation for synovial fluid harvest that is beyond the risk or instrumentation/manipulation of the indicated surgical procedure. Joint aspirates will then be stored until A2M assay.

Inclusion Criteria:

Group 1, Non-traumatic primary OA:

1. Subject scheduled to undergo primary unilateral total knee arthroplasty for primary osteoarthritis as determined by an orthopedic surgeon
2. Subject is male or female over 45-75 years of age
3. Subject is able to read and understand informed consent form and must subsequently sign and date consent form

Group 2, Secondary post-traumatic/overuse OA:

1. Subject scheduled to undergo unilateral total knee arthroplasty secondary osteoarthritis as determined by an orthopedic surgeon, which MUST include either previous injury or surgery to the operative knee.
2. Subject is male or female 45-75 years of age
3. Subject is able to read and understand informed consent form and must subsequently sign and date consent form

Exclusion Criteria:

Group 1, Non-traumatic primary OA:

1. History of inflammatory arthritis (e.g. rheumatoid arthritis, ankylosing spondylitis)
2. Indication for surgery other than osteoarthritis
3. Revision total knee arthroplasty
4. Age >75, age <44
5. Unable to read, understand, or sign informed consent form
6. Previous knee infection
7. Congenital disorders of the knee, calcium pyrophosphate dehydrate deposition disease

Group 2, Secondary post-traumatic/overuse OA:

1. History of inflammatory arthritis (e.g. rheumatoid arthritis, ankyolosing spondylitis)
2. Indication for surgery other than osteoarthritis
3. Age >75, age <44
4. Unable to read, understand, or sign informed consent form
5. Previous knee infection
6. Congenital disorders of the knee, calcium pyrophosphate dehydrate deposition disease