Disease Processes of  Synovial Membrane, Fibrous Capsules, Ligaments, Articular Cartilage

Scientists' understanding of non-infective arthritis dramatically advances every year, and each year when the American Association of Equine Practitioners (AAEP) meets, practitioners have the opportunity to absorb the newest information on these perplexing diseases presented by some of the veterinary community's most respected joint disease specialists.

C. Wayne McIlwraith, BVSc, PhD, FRCVS, Dipl. ACVS, Professor and Director of Orthopaedic Research at Colorado State University (CSU), and past president of the American Association of Equine Practitioners, reviewed the relevant anatomy and physiology of joint structures, the pathobiology of joints, and their reaction to insult and injury (including synovitis and capsulitis). New understanding of proteinases, prostaglandins, free radicals, and cytokines was reviewed, as were the morphologic and biochemical responses of articular cartilage to insult. McIlwraith also provided information on new recognition of the pathologic process of osteophyte and enthesophyte formation.

Subchondral Bone and Joint Disease

"Regardless if he's a trail horse or a race horse, bone remodels quite quickly," said Christopher E. Kawcak, DVM, PhD, Dipl. ACVS, Assistant Professor at CSU. He explained the evidence suggesting that osteochondral diseases in the athletic horse start as chronic processes that culminate in clinical disease. "Our current understanding of osteochondral disease is based on clinical and pathologic sources," he explained in his paper, "and the lack of information about joint tissue adaptation and disease has hampered objective studies of osteochondral tissues."

"We'd like to determine when bone adaptation may lead to disease," Kawcak said, "and we're thinking that there may be a threshold to where that adaptation leads to disease process. If that threshold does exist, it would be nice to diagnose it. The key to early diagnosis lies in detecting those early changes."

Currently, the causes of osteochondral injuries are hard to determine, and disease is even more difficult to detect at an early stage. Only when the pathogenesis of such diseases is known and completely understood will there be any hope of identifying diagnostic means of early identification.

Diagnostic Imaging

"With the newer imaging techniques, we're often better able to characterize what occurs in the subchondral bone and the joint itself," said Kawcak. Veterinarians were once limited to radiography and clinical examination to detect early, subtle joint disease, but the advancement of computed radiography, gait analysis, understanding of biochemical markers, scintigraphy, magnetic resonance imaging (MRI), computed tomography, and biomechanical modeling have changed this.

In order to completely characterize joint disease, there must be the capability to measure the mechanical forces on and within the joint, tissue architecture and geometry, tissue matrix properties, and the level of inflammation in the joint.

Kawcak discussed the current state of diagnostic capabilities to detect pathologic changes in osteochondral tissues typical of joint disease, and then explained new techniques. He suggested the need for MRI to be used in diagnostics of any joint problem, and mentioned that intraoperative assessment of osteochondral tissues is being explored.

Synovial Fluid and Serum Markers for Diagnostics

"Diagnostic arthroscopy is still the gold standard," said McIlwraith before expanding on the complex and exciting prospect of using synovial fluids and serum markers to predict joint arthritis or injury.

Conventional analysis of synovial fluid has been around for awhile-- while normal synovial fluid is clear and pale, abnormal fluid appears blood-streaked, indicative of hemorrhage. But analysis techniques have advanced considerably. "We are progressing and finding which (markers) are most useful and on which ones we want to concentrate," said McIlwraith. "It is unlikely that one marker will be the 'magic bullet,' but with careful examination of a series of markers in the light of specific disease processes, the use of markers for the diagnosis and monitoring of joint disease is not unrealistic," he added.

Gene Therapy for Osteoarthritis

"Many recognized disease states relate to a lack of, a defect in, or an imbalance of a particular protein(s)," began David Frisbie, DVM, PhD, Dipl. ACVS, Manager of the Equine Orthopaedic Research Laboratory at CSU. "Since the gene is the basal unit ultimately responsible for protein production, it is also a logical therapeutic target. Currently, most gene therapy protocols are directed towards increasing levels of selected therapeutic proteins in an attempt to alter specific disease processes.

"Gene therapy is commonly defined as the use of molecular methods to replace  defective or absent genes, or to counteract those that are overexpressed," Frisbie explained." There are three stages to this process: Isolation of the genes responsible for the protein(s) of interest, manipulation of those genes, and transference of the manipulated genes into host cells.

There are two methods of transferring manipulated genes into host cells: Ex vivo transfer, in which cells are collected from a patient, engineered and tested in the laboratory; and in vivo--with delivery vectors (modified viral or non-viral). The ex vivo method allows for more safety via testing, but the in vivo method is very easy to use.

Frisbie ended his talk with this quote from another in the field: "In every field of medicine, the ability to give the patient therapeutic genes offers extraordinary opportunities to treat, cure, and ultimately prevent a vast range of diseases that now plague mankind."

Metalloproteinase Inhibitors

"There is a clear need for new therapeutic approaches that block precise steps in the disease processes (of equine traumatic arthritis and osteoarthritis or OA), and there has been development of these in recent years," began McIlwraith in a presentation on metalloproteinase inhibitors.

The degradation of collagen, a major structural component of cartilage, in the final stage of osteoarthritis and traumatic joint injury is believed to be a permanent change leading to irreversible damage. McIlwraith said that the initial degradation is reasonably accepted to be associated with matrix metalloproteinase (MMP) enzymes. Thus, inhibiting the effect of these enzymes could help protect against collagen degradation.

Research to clarify the safety and efficacy of MMP inhibitors is ongoing, but McIlwraith suggested the following target requirements for their safe use as therapy:

  • Oral bioavailability (peptide-based inhibitors are rapidly degraded and inactivated in the GI tract);
  • Targeting and penetration of cartilage;
  • Nonantigenic (nonimmunogenic);
  • Broad-spectrum (with increased side effects) vs. MMP-specific agents (must decide which MMPs are important);
  • Concomitant therapy (non-steroidal anti-inflammatory drugs, analgesics); and
  • Noninvasive monitoring of therapeutic response (with markers and imaging).

Articular Cartilage Repair

Following injury to articular (joint surface) cartilage, "repair tissue is biomechanically inferior to normal articular cartilage," said Alan J. Nixon, BVSc, MS, Dipl. ACVS, of Cornell University. Thus, researchers are trying to find ways to improve medical and surgical treatment.

Two methods Nixon described are microfracture/micropick and cartilage flap reattachment. Microfracture involves accessing the better-healing subchondral bone beneath articular cartilage with micropicks, which results in increased tissue volume and some collagen improvement. This slight improvement might prolong active exercise.

Cartilage flap reattachment can be done when the flap is not completely detached. It involves arthroscopic debridement of necrotic tissue and pinning of the flap to the bone below. "Resolution of joint effusion and radiographically obvious subchondral lysis, as well as reformation of the subchondral contour, are better than that following cartilage flap removal," said Nixon.

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