Joint pharmacology is an often-overlooked area of research, despite the clear need for novel treatments for a range of disorders. The overall burden of musculoskeletal disease to society is enormous with the majority of elderly people affected. A large part of this is arthritis; the two most common subtypes of which are rheumatoid arthritis (RA), an autoimmune disease that typically progresses to all joints and osteoarthritis (OA), a condition with multiple and less well-defined aetiologies. Although the global prevalence of RA itself is modest (0.24%), the disease is severe and protracted and is therefore a major contributor to pain and disability accounting for approximately 5 million disability-adjusted life years (DALYs) in 2010[
18]. In 2002 WHO ranked OA and RA as the first and second largest individual causes of "years lived with disability" (YLD)[
19] and the more recent and comprehensive 2010 Global Burden of Disease study placed musculoskeletal disorders as the largest contributor (23.2%) to YLD in the world apart from mental health conditions[
20].
Synovitis is increasingly viewed as a pathogenic factor in arthritic diseases. In OA, synovitis is common[
13,
21,
22], but in RA it is the central component[
23,
24]. A number of potential treatments are available to reduce pain generally (NSAIDs or paracetamol), or inflammation in RA and OA however control of rheumatic pain specifically is difficult. Latest treatments for RA include biological interventions that interfere with TNF-α signalling and the recent discovery of interactions between cartilage and subchondral bone[
25] mediated by NGF and the FGF family of peptides has brought some excitement to treatment of OA in particular[
26]. Both sprifermin (human recombinant FGF-18) and tanezumab (anti-NFG monoclonal antibody)[
27] are both showing promise. Non-peptide drugs are also frequently advantageous over peptides due to their (often) greater ease of preparation and usage. The synovium contains sensory nerve endings however and a clear source of pain; probably in both RA and OA. Whilst a considerable amount is known about the pharmacology of chondrocytes[
28], considerably less is known about equally important synovial cells. In fact the synovium as a whole has received less attention that the other joint tissues, partly due to its relative inaccessibility and fragility in a typical rodent model. Interestingly, however, the major cellular component of the normal synovium is type B or fibroblast-like synoviocyte (FLS) and these can be isolated from humans[
29] and larger animals[
30], but even relatively straightforwardly, from rodents[
31]. A well-established contributor of joint inflammation is the infiltration of synovial macrophages. Macrophages express CB
2 receptors, and additionally, cannabinoid receptors are expressed on neuronal cells. Therefore there is scope for a complex pattern of cannabinoid interactions within the synovium and surrounding joint tissue. Fukoda
et al[
17] now test the efficacy of the 200 fold selective CB
2 agonist JWH133 against both FLS inflammation and the murine collagen type II (CII)-induced arthritis (CIA) model of RA. They find widespread and encouraging results.
In vitro, they culture FLS from RA patients and show that FLS produce IL-6, MMP-3, and CCL2 (also known as monocyte chemotactic protein, MCP-1) in response to TNF-α stimulation. This is interesting at a number of levels; IL-6 is known to induce pain[
32,
33]. MMP-3 has roles in matrix turn over and may diffuse from the synovium into cartilage in parallel to MMP-13[
34]. CCL2 is known to be elevated in RA samples[
35], this is a chemokine often referred to as MCP1 and is involved in the recruitment of monocytes, macrophages, T-cells and dendritic cells to the sites of inflammation. Fukoda
et al[
17] also showed how the promising JWH133 was able to inhibit CCL2 expression. There were other observations too. For example, JWH133 inhibited markers of osteoclastogenesis and this too could have implications for preservation of bone loss in RA. Osteoclastogenesis is a multi-complex procedure that includes many stages, and each one of which is a potential therapeutic target in OA[
36] and many other diseases including osteoporosis[
37]. This is an additional promising role for JWH133 and fits nicely with the observation CB
2-deficient mice develop osteoporosis with age[
37] and that JWH133 attenuated pain behaviours in a rat model of OA[
38]. Fukuda
et al observed[
17] an over-all reduction in arthritic "score" in CIA mice injected with JWH133 compared to controls, again enforcing the potential for JWH133.