Research Review By Dr. Ceara Higgins©

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Date Posted:

August 2017

Study Title:

Degenerative Joint Disease and Neuroinflammation

Authors:

Fusco M, Skaper SD, Coaccioli S, et al.

Author's Affiliations:

Scientific Information and Documentation Center, Epitech Group; University of Padua, Padua; Santa Maria Hospital, University of Perugia, Terni; School of Dentistry, LUdeS University, La Valletta, Malta; Paolo Procacci Foundation and European League Against Pain, Rome; University of L’Aquila, Italy

Publication Information:

Pain Practice 2017; 17: 522-532.

Background Information:

Osteoarthritis (OA) and rheumatoid arthritis have a significant impact on society. OA is associated with degeneration of joint cartilage and/or menisci, subchondral sclerosis, and synovial membrane inflammation. This can ultimately result in a ‘bone-on-bone’ scenario, resulting in friction, pain, trauma, and ligament damage. Rheumatoid arthritis (RA) is a chronic systemic disease which leads to pain and eventual deformity.

Both conditions, but particularly OA, can no longer be simply thought of as a ‘degenerative’ process. There is a growing body of evidence to support the role of inflammation – both locally and systemically – in promoting damage in the joints and bones which leads to joint-related functional deficits. This narrative review paper discussed the neuroinflammatory contribution to the development of tissue damage and joint-related pain, as well as prospects for innovative treatment to slow progression of these diseases by controlling neuroinflammation.

Summary:

Cross-talk between articular cartilage and subchondral bone is the backbone of joint diseases:

It has long been thought that rheumatic and musculoskeletal diseases were centered in the joint cartilage. However, recent research has suggested that subchondral bone also plays a significant role (5). 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 (2).

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 (1).

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 that leads to cartilage degradation. This tissue damage then triggers an inflammatory reaction involving the synovia and rapidly activates articular mast cells, which drive the inflammatory response. Finally, osteoblasts in patients with osteoarthritis show a change in chondrocyte phenotype in favour of hypertrophic differentiation and matrix mineralization (4).

Articular Mast Cells:

Mast Cells as Coordinators of Cross-talk Between Articular Cartilage and Subchondral bone, Neuroinflammation, and Pain:
Cross-talk between subchondral bone, cartilage, and synovia is primarily mediated by cytokines and growth factors, which originate primarily from mast cells. Mast cells also coordinate the neuroinflammatory process and are located mainly in the synovial membrane, joint capsules (5), along blood vessels and nerve endings (7). In early stage joint disease, we see increases in mast cell density, especially in the synovial membrane. We also see hyperplasia and hyperactivation of mast cells, which correlates with the appearance of the pathogenic hallmarks of osteoarthritis (6). Mast cells release mediators that have specific actions in joint inflammation and degenerative-destructive processes (9). These include the stimulation of synovial fibroblast proliferation, production of metalloproteinases, and the upregulation of histamine H1 receptors by histamine (10), and the inhibition of fibroblast apoptosis by mast cell tryptase (11).

The synovial tissue of patients with rheumatoid arthritis or osteoarthritis show significant increases in tryptase type (12). This can activate the latent forms of MMP-3 and pro-MMP-13 (MMP = matrix metalloproteinase), both of which can degrade aggrecans (a principle component of the cartilage matrix), leading to fragments of aggrecans floating in the synovial fluid which are unable to bind to hyaluronic acid (13).

These mast cell mediators therefore contribute to a significant reduction in the viscoelasticity of the synovial fluid, as a result of reduced concentrations and reduced average molecular weight of hyaluronic acid (14). Mast cells also indirectly influence degradation of hyaluronic acid via proinflammatory mediators including histamine, prostaglandin D2, cytokines, and chemokines, which can interact with fibroblasts, synoviocytes, and chondrocytes (15).

The rapid release of mast cell histamine can lead to tissue edema and destruction of the stromal matrix through activation of endothelial cell H1 receptors. As well, the release of growth factors from mast cells could contribute to the development of angiogenic processes that are typical of joint diseases (8). Mast cell-derived nerve growth factor (NGF) interacts with receptors on sensory nerve endings and triggers a series of processes that alter cellular activity and amplify pain. Antidromic release of neuropeptides causes neurogenic inflammation in tissue (17), which amplifies the inflammatory process in the joints and feeds joint neurogenic pain (19). In osteoarthritis there is a direct correlation between synovial neuropeptide concentration, severity of synovitis, and the extent of joint pain, which confirms an inter-relationship between sensory nerve activation and inflammation (20). This leads to a lowering in the threshold of neuronal activation, leading to the neuron becoming receptive to stimuli that are not normally painful; a condition known as central sensitization (3).

Many mast cell receptors may activate their cognate receptors on sensory nerve endings, contributing to the development of peripheral sensitization (16). Osteochondrophytes, bone microfractures, and bone marrow hypertension in joint diseases can induce stretching/compression, leading to an abnormal mechanical stress-irritation and persistent peripheral sensitization.

Mast Cells as Communicators of Microglia and Promoters of Central Sensitization:
The mast cell-microglia axis supports inflammation of the central and peripheral nervous systems and can be related to chronic pain in joint diseases. Peripheral mast cells use chemical mediators to interact with spinal and supraspinal ganglionic microglia directly and somatosensory neurons to interact indirectly (18). At the level of the spine, microglia become activated, astrocytes increase in number, and the production of proinflammatory cytokines increases, which suggests that changes in glia are both morphological and functional (23). In situations where abnormal IL-1 expression in the spinal cord is induced, a condition similar to arthritis is found. This confirms the existence of cross-talk between the spinal cord and joints and shows that peripheral signals can lead to changes at the level of the spine and alterations in the central immune system can modify peripheral processes (24). As well, patients with osteoarthritis have shown central sensitization, with decreased pain thresholds to pressure and prick stimuli (22) that are unrelated to radiological findings. This suggests that central sensitization contributes significantly to osteoarthritis-related pain (22).

This evidence leads to the inescapable conclusion that joint pain is not of a single typology, but rather is associated with a variety of different mechanisms that are primarily of a nociceptive/inflammatory and neuropathic nature (25). Further, abnormal mechanical-irritative stress acting on the nerve fibers of the joint can facilitate the development of the neuropathic component (27), and mast cells appear to be directly involved in neuropathic pain (28), with direct damage to nerve fibers triggering degranulation of mast cells (26).

Potential new targets for the treatment of degenerative joint diseases:

Currently, treatments for rheumatic and articular disease are mainly aimed at symptomatic relief and have limited effect on the progression of the disease. Some new drugs aimed at preserving the joint structures have been investigated, but clinical investigation has been largely stopped due to adverse effects, leaving limited treatment options available now (29).

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 (21), which suggests that PEA might have a protective role in joints. Therefore, PEA supplementation may be beneficial to individuals with those conditions. As well, PEA supplementation shows anti-inflammatory and analgesic effects in conditions with chronic inflammation (31), modulates mast cell degranulation, reduces activation of spinal cord microglia (33), reduces chronic and neuropathic pain associated with a variety of pathologies (30), and reduces pain and improves function in patients with temporomandibular disorders (34).

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 (PPAR & PPAR) have also been proposed as potential targets for joint diseases, with studies suggesting that PPAR agonists reduce synthesis of inflammatory and catabolic agents, preventing cartilage lesions.

Clinical Application & Conclusions:

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. A loss of balance between these two structures in cases of joint disease becomes amplified by the presence of mast cells, the degranulation of which is associated with alterations of all joint structures. As well, persistent activation of mast cells expedites the proliferation of spinal neuroinflammation.

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. (Reviewers note: PEA is available online in 400mg capsules. It is suggested that dosage can be increase up to 1200mg per day in a stepwise fashion.)

EDITOR’S NOTE: The authors of this paper were researchers and medical doctors with expertise in pharmacology, anesthesiology and rheumatology. As such, they did not explore the treatment literature on manual medicine.

Study Methods:

This study is a narrative review of the evidence. As such, no formal study methods were reported.

Study Strengths / Weaknesses:

As this was a narrative literature review there is a possibility of selection bias in how the authors chose their literature citations.

Additional References:

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