Discussion

Introduction:
To understand the medical basis of treating lameness in the horse an understanding of the pathophysiological events of the causes of lameness is fundamental. In this respect, both the correct choice of treatment as well as the correct timing of treatment can be envisaged, thus maximising the ability to influence (or modify) the disease process. The use of 'disease-modifying drugs' is therefore the primary aim in that treatment results in a positive effect on the disease process.

Joint disease:
Joint disease is the most common cause of lameness in horses and osteoarthritis (OA) is the main condition encountered. Osteoarthritis is characterised by a progressive loss of articular cartilage accompanied by new bone formation and synovial proliferation resulting in pain, loss of joint function and hence lameness. Risk factors, such as age, sex, genetics and lifestyle are documented in human literature but difficult to characterise in the horse. Some studies, for example distal tarsal joint disease in Icelandic horses, show strong genetic basis for joint disease but large studies of risk factors in the horse are lacking.

Events occurring in osteoarthritis:
OA is primarily characterised by progressive degenerative loss of articular cartilage matrix but it is important to realise that events affecting subchondral bone, synovial membrane and supporting joint capsule play important roles in the pathobiology of this disease. Additionally, although traditionally thought of as a degenerative condition, OA has important inflammatory components involving key pro-inflammatory cytokines, such as interleukin-1 (IL-1) and activation of proteolytic enzymes, such as the matrix metalloproteinases (e.g. MMP-13) and aggrecanases (e.g. ADAMTS-4 and -5).
Normal cartilage turnover occurs slowly and is regulated by articular chondrocytes embedded within the matrix. Catabolic events lead to breakdown of extracellular matrix molecules, particularly collagen and proteoglycans by MMPs and ADAMTS enzymes. Attempted repair processes occur but result in alteration in expression of structural proteins and dysregulation of growth factors and can inadvertently exacerbate the situation. Further to this, alterations in the joint environment, such as hypoxia and acidosis lead to changes in gene expression and regulation of inflammatory enzyme activity.
In addition to cartilage changes, osteophyte formation and subchondral bone sclerosis are recognised features of OA. Osteophytosis may be as a result of inappropriate growth factor expression (e.g. TGF-beta) and formation of new bone at the peripheral margins of joint results in reduced range of motion and pain. Microfractures in the subchondral bone occur due toabnormal loading through the joint and lead to sclerosis and altered biomechanical forces through the articular cartilage. Whether subchondral bone changes precede or follow articular cartilage changes is not fully known but micro-architectural changes and differential gene expression impact directly on cartilage integrity. Finally, the activated synovium is an important source of inflammatory cytokines, enzymes and reactive oxygen and nitrogen species.

Medical options in joint disease:
By understanding the pathobiology behind OA, therapeutic targets can be realised. Treating the diseased joint as an integrated process with temporal features lends credence to targeted multimodal approach.

NSAIDs:
Nonsteroidal anti-inflammatory drugs inhibit the cycloxygenase pathway involved in prostaglandin production. The COX-2 isoform is mainly involved in the inflammatory response and the use of 'COX-1 sparing' NSAIDs (such as carprofen and firocoxib) may reduce risk of side effects. NSAIDs result in reduction of inflammation and pain but their long-term effect on cartilage has been questioned. Local application of topical NSAIDs (diclofenac) also reduces joint inflammation in an OA model.

Corticosteroids:
Despite the advance in understanding the pathophysiology of joint disease, corticosteroids remain important and effective drugs in treatment of osteoarthritis. They have a wide range of anti- inflammatory effects and repress of genes encoding multiple inflammatory mediators including cytokines, phospholipase A2, iNOS, COX-2 and adhesion molecules.

PSGAGs:
Polysulphated glycosaminoglycans have anti-inflammatory activity and inhibit degradative proteolytic enzymes. They are claimed to be 'cartilage-protecting' but although reductions in cartilage erosion and GAG loss have been shown, its use prophylactically to protect cartilage has not been proven.

Hyaluranic acid (HA):
Hyaluronic acid is a key component of synovial fluid and extracellular matrix. It has anti-inflammatory properties due to steric hindrance and/or receptor binding on cell surfaces. Chronic OA usage may be limited and it is often combined with corticosteroids but in acute synovitis/early OA it may be effective where modulation of acute inflammatory mediators reduce inflammation.



IL-1 receptor antagonists:
The binding of IL-1 to the IL-receptor results in activation of intracellular signalling cascades and release of inflammatory cytokines and enzymes. A number of endogenous IL-1 inhibitory pathways exist, the most important of which is IL-1RA (IL-1 receptor antagonist). This binds to IL-1 receptor and is produced by chondrocytes to sustain cartilage integrity. IL-1ra gene vector therapy has been shown to reduce experimentally induced OA. Autologous conditioned serum is used in treatment of joint disease where co-incubation of peripheral blood with chromium sulphate increases expression of IL-1RA without concomitant increases in IL-1 or TNF-alpha.

Tiludronate:
Bisphosphonate use in joint disease has the basis that subchondral bone changes are an important part of the pathophysiology of OA. Studies show reduced lameness scores in horses with distal tarsal joint OA and reduced periarticular osteophytosis in treated horses.

Platelet rich plasma (PRP):
Platelet rich plasma (PRP) results in elevated concentrations of a number of growth factors including IGF-1, TGF-beta, PDGF and VEGF and has been used in tendon/ligament injuries and in bone defects. Few studies exist investigating the clear benefits of PRP in joint disease. Small studies claim to show significant reductions in joint effusion and lameness in joint disease but other studies have shown no positive effects on cartilage repair in acute chondral defect models.

Nutraceuticals:
Although some evidence exists to the use of nutraceuticals and joint disease, queries regarding the constituent parts and low bioavailability make true scientific conclusions to efficacy hard to resolve. Symptomatic improvements have been documented and popularity with horse owners will support their continued use.