The structural determinants of pain and mechanical dysfunction in OA are also not well understood, but are believed to involve multiple interactive pathways. Articular cartilage is both aneural and avascular. As such, cartilage is incapable of directly generating pain, inflammation, stiffness, or any of the symptoms that patients with OA typically describe (22
). Given its relative unimportance to OA’s symptomatic presentation, it is ironic that articular cartilage has received so much attention while other common symptom sources in the joint are ignored.
In contrast the subchondral bone, periosteum, periarticular ligaments, periarticular muscle spasm, synovium and joint capsule are all richly innervated and are the source of nociception in OA.
In population studies there is a significant discordance between radiographically diagnosed OA and knee pain (7
). Whilst radiographic evidence of joint damage predisposes to joint pain, it is clear that the severity of the joint damage on the radiograph bears little relation to the severity of the pain experienced.
However, utilising other imaging modalities such as magnetic resonance imaging (MRI) significant structural associations such as bone marrow lesions (23
), sub-articular bone attrition (25
), synovitis and effusion (26
) have been related to knee pain. It remains unclear which of these local tissue factors predominate as until recently these analyses did not account for the fact that much of the structural change is collinear (a person who has more severe disease will have worse structural change in multiple tissues including the bone synovium, etc) and were not adjusting for other tissue changes. A recent analysis confirmed most beliefs that it is likely that changes in the subchondral bone and synovial activation/ effusion predominate (28
Lesions in the bone marrow play an integral if not pivotal role in the symptoms that emanate from knee OA and its structural progression (23
). Bone marrow lesions were found in 272 of 351 (77.5%) persons with painful knees compared with 15 of 50 (30%) persons with no knee pain (P < 0.001). Large lesions were present almost exclusively in persons with knee pain (35.9% vs. 2%; P < 0.001). After adjustment for severity of radiographic disease, effusion, age, and sex, lesions and large lesions remained associated with the occurrence of knee pain. More recently their relation to pain severity was also demonstrated (24
). Other bone-related causes of pain include periostitis associated with osteophyte formation (29
), subchondral microfractures (30
), and bone angina due to decreased blood flow and elevated intraosseous pressure (31
). The particular bone pathology most responsible for pain remains elusive however identifying this would be a major advance in delineating appropriate therapeutic targets. One likely source that remains underexplored is that of intra-osseous hypertension. The pathophysiology remains unclear, although phlebographic studies in OA indicate impaired vascular clearance from bone and raised intra-osseous pressure in the bone marrow near the painful joint (31
). What may subsequently cause pain is as yet unknown. Increased trabecular bone pressure, ischemia and inflammation are all possible stimuli.
The synovial reaction in OA includes synovial hyperplasia, fibrosis, thickening of synovial capsule, activated synoviocytes and in some cases lymphocytic infiltrate (B- and T-cells as well as plasma cells) (35
). The site of infiltration of the synovium is of obvious relevance as one of the most densely innervated structures of the joint is the white adipose tissue of the fat pad which also show evidence of inflammation and can act as a rich source of inflammatory adipokines (36
). Synovial causes of pain include irritation of sensory nerve endings within the synovium from osteophytes and synovial inflammation that is due, at least in part, to the release of prostaglandins, leukotrienes, proteinases, neuropeptides and cytokines (37
). Synovitis is frequently present in osteoarthritis and may predict other structural changes in osteoarthritis and correlate with pain and other clinical outcomes (26
). Synovial thickening around the infra-patellar fat pad using non-contrast MRI has been shown on biopsy to represent mild chronic synovitis (39
). A semi-quantitative measure of synovitis from the infrapatellar fat pad is associated with pain severity and similarly change in synovitis is associated with change in pain severity (27
Another source of joint pain in OA may be from the nerves themselves. Following joint injury in which there is ligamentous rupture, the nerves which re-innervate the healing soft tissues contain an overabundance of algesic chemicals such as substance P and calcitonin gene-related peptide. An interesting observation of these new nerves was that their overall morphology was abnormal with fibres appearing punctate and disorganised (40
). Since these phenomena are consistent with the innervation profiles described in nerve injury models, we speculate that injured joints may develop neuropathic pain post-trauma. Indeed, treatment of inflamed joints with the neuropathic pain analgesic gabapentin can also relieve arthritis pain (42