|Study title: Degenerative Joint Disease and Neuroinflammation
Authors: Fusco M, Skaper SD, Coaccioli S, et al.
Publication information: Pain Practice 2017; 17: 522-532.
It has long been thought that rheumatic and musculoskeletal diseases were centered in the joint cartilage. However, recent research suggested that subchondral bone also plays a significant role. Studies using MRI have shown that changes in subchondral bone, including thickening, reduced flexibility, and reduced trabecular density, may be significant in osteoarthritis and microcrystalline arthropathy development. In some cases, there is evidence that these types of subchondral bone changes may precede cartilage injury.
Recently, a systematic review confirmed an association between bone lesions, osteophytes, and changes in bone morphology, independently from one another with structural osteoarthritis progression and joint replacements. An association was also found between bone lesions and changes in bone morphology and pain related to osteoarthritis in the knees, hands, and hips. Together, this points to robust cross-talk between the articular cartilage and subchondral bone in cases of joint disease.
During periods of elevated subchondral bone turnover, cytokines and trophic factors are released and interact with articular cartilage, creating a positive feedback loop between cartilage damage and the bone healing process. When stimuli such as inappropriate loads or the presence of subchondral bone catabolic factors affect chondrocytes, they undergo a change in phenotype and begin to produce cytokines and chemokines. These then act in a paracrine fashion (exerting its effect in the immediate vicinity), initiating a vicious cycle leading to cartilage degradation. This tissue damage then triggers an inflammatory reaction involving the synovia and rapidly activates articular mast cells. Finally, osteoblasts in patients with osteoarthritis show a change in chondrocyte phenotype in favour of hypertrophic differentiation and matrix mineralization.
New targets for treatment
Mast cells and microglia at the cellular level can be modulated to attack both peripheral and central neuroinflammation, reducing pain and promoting restoration of tissue homeostasis, limiting disease progression. This makes them very attractive targets for medical intervention. Synovial fluid shows drastically reduced levels of N-palmitoylethanolamine (PEA) in patients with osteoarthritis or rheumatoid arthritis, which suggests that PEA might have a protective role in joints. Therefore, PEA supplementation may be beneficial to individuals with those conditions. PEA supplementation also shows anti-inflammatory and analgesic effects in conditions with chronic inflammation, modulates mast cell degranulation, reduces activation of spinal cord microglia, reduces chronic and neuropathic pain associated with a variety of pathologies, and reduces pain and improves function in patients with temporomandibular disorders.
Cannabinoid receptor CB1 and CB2 agonists have a protective role in joint diseases. CB1 intervenes in bone remodelling and age-dependant bone loss, while CB2 protects against bone loss, and endows immune cells with immunomodulatory and anti-inflammatory activities. Substances such as PEA activate CB2 receptors, making them good options for the treatment of rheumatic diseases.
Peroxisome proliferator-activated receptors alpha and gamma have also been proposed as potential targets for joint diseases, with studies suggesting that their agonists reduce synthesis of inflammatory and catabolic agents, preventing cartilage lesions.
Pain resulting from joint disease comes from both inflammatory and neuropathic components. There is still no clear pathogenesis of joint disease, however, the prevailing consensus supports underlying cross-talk between cartilage and subchondral bone.
Disease-modifying drugs, specifically those capable of counteracting disease progression, should be the future focus of research. These include molecules targeting cannabinoid receptors (such as PEA) and PPARs. This research could change the focus of osteoarthritis and rheumatoid arthritis treatment from symptomatic relief to maintaining or even reversing joint damage.