Editorial:
Osteoarthritis as an Autoinflammatory Disease Caused
by Chondrocyte-mediated Inflammatory ResponsesThis section is compiled by Frank M. Painter, D.C.
Send all comments or additions to: Frankp@chiro.org
FROM: Arthritis & Rheumatism 2012 (Mar); 64 (3): 613–616 ~ FULL TEXT
OPEN ACCESS Y. T. Konttinen, T. Sillat, G. Barreto, M. Ainola and D. C. E. Nordström
Helsinki University Central Hospital,
Helsinki, Finland
Osteoarthritis (OA) is considered to be primarily a disease of the hyaline articular cartilage, which secondarily affects subchondral bone and synovial membrane. The exact nature and mechanisms of OA, particularly during the early phases of the disease, are unknown. OA per se might in part relate to the poor inherent repair capacity of the articular cartilage, which during the lifetime of modern (long-lived) human beings, is gradually subjected to progressive and accumulative wear and tear. However, the idea of OA as a simple wear-and-tear disease has been widely rejected because various biologic processes, such as inflammation and enzymatic cartilage degradation, are apparently involved in its pathogenesis. Recent findings provide possible new explanatory pathogenic models that intimately link the two phenomena—biomechanical wear and tear of the cartilage (osteoarthrosis) and inflammation (osteoarthritis)—to each other.
Although mesenchymal progenitor cells have been found in the cartilage matrix [1], cartilage cannot recruit circulating mesenchymal stem cells and is unable to organize the repair according to the developmental programs that, during the embryonic and fetal stages, created the delicate molecular collagen and architectural tissue structure of true synovial diarthrodial joints. Structural degeneration, cartilage thinning, and sclerosis of the subchondral bone plate are indeed common in the elderly population, but clinically manifest OA with pain is, fortunately, much rarer. This depends in part on the avascular nature of the cartilage; cartilage contains neither blood nor lymphatic vessels. This makes it impossible for the cartilage to recruit leukocytes and, according to the conventional view, makes it unable to mount an inflammatory response that is recognizable by the classic signs of redness, local inflammatory swelling, pain, increased local temperature, and impaired function. The question is whether cartilage can mount an inflammatory cellular (chondrocyte) response, which then via transfer of the locally produced messenger molecules to synovium causes synovitis, with classical signs of inflammation.
Cartilage is also aneural, which might be useful from the functional point of view, considering the high peak loads and trauma that the cartilage covering the ends of the bone is naturally subjected to during cyclic activities and traumatic “high-energy” activities in particular. Due to the lack of primary afferent nociceptive nerves, cartilage also cannot be a source of nociceptive or inflammatory pain. Pain in OA is therefore considered to be caused by secondary involvement of the synovium, that is, osteoarthritic synovitis, which has an unclear pathogenesis. In any case, it has been emphasized that the lymphocyte-rich mononuclear cell infiltrates seen in OA are relatively similar to those seen in rheumatoid arthritis (RA) and that, at the superficial level at least, the differences between secondary OA synovitis and primary RA synovitis are quantitative rather than qualitative.
The results reported by Opolka and coworkers [2] elsewhere in this issue of Arthritis & Rheumatism can be used to question this line of speculation. The investigators show that both in micromass and monolayer culture, primary costal chondrocytes from newborn mice produce neuronal transmitters, substance P (SP), and some of them probably also norepinephrine (NE) (because they contained tyrosine hydroxylase, the rate-limiting enzyme of its biosynthesis). Furthermore, chondrocytes contain neurokinin type 1 (NK-1) receptor and α-adrenergic (possibly all α subtypes, although monolayer cultures did not contain α1a or α2c) and β-adrenergic (β1–β3) receptors, so they can themselves also respond in an autocrine and paracrine mode to the agents they produce. Substance P and NE did not affect the collagen or proteoglycan (extracellular matrix [ECM]) synthesis, but SP, via the NK-1 receptors, dose-dependently increased the proliferation of chondrocytes, while NE decreased apoptosis by stimulating β-adrenergic receptors. Further, both neurotransmitters increased the formation of focal adhesion contacts, which are necessary for the prevention of anoikis (chondroptosis).
If one raises one’s gaze beyond the local chondrocyte horizon, potential distant effects of chondrocyteproduced mediators come to mind. Because of the above-mentioned lack of blood and lymphatic vessels in the cartilage tissue, these locally produced and potentially proinflammatory and algogenic substances are not carried away from the cartilage to the systemic circulation. Cartilage is cell poor, because chondrocytes only occupy ~1–2% of the total cartilage volume, and therefore, the on-site consumption of chondrocyte mediators is relatively minor. Thus, they are not necessarily diluted or consumed to subthreshold levels, but can, via interstitial tissue fluid and synovial fluid, access cells in the synovial membrane, in particular synovial lining cells and sublining tissues. Indeed, many of these substances have been described in the synovial fluid transit compartment, but envisioned to have originated from the synovial membrane, not the cartilage itself.
The synovial lining is composed of macrophage-like type A lining cells and fibroblast-like type B lining cells. Sublining tissue contains polymodal unmyelinated primary afferent nociceptive nerves and is richly vascularized by a microvascular network, which forms a potent transendothelial exit route for circulating leukocytes to synovial tissue upon inflammatory activation of the endothelial cells to express vascular endothelial cell adhesion molecules. Therefore, the chondrocyte-mediated local synthesis and release of proinflammatory and algogenic agents suggests that the avascular cartilage, in spite of the lack of blood vessels, lymphatic vessels, and primary afferent nociceptors, could nevertheless contribute to an inflammatory process and pain in synovial membrane. Not only would it be possible for the cartilage-derived mediators to perpetuate or enhance an already ongoing process, but according to the scenario described, inflammatory responses in the cartilage could form the primary event in this sequence, as described below.
Table 1
Table 2 Chondrocytes are best known for their role in the synthesis of the cartilage ECM, for example, highly negatively charged aggrecan proteoglycans providing swelling pressure to the cartilage matrix, types II, IX, and XI collagen in the collagen network exerting counterpressure and confining osmotic swelling, and cartilage oligomeric matrix protein and leucine-rich repeat proteins crosslinking collagen fibers, which enforces the mechanical strength of the collagen network. Chondrocytes are a potential source of several proinflammatory and algogenic substances, some of which are mentioned in Table 1. It should be noted that inflammation of the cartilage leads to local production of molecules that can sensitize (e.g., tumor necrosis factor α [3]) and/or directly (or indirectly) stimulate primary afferent nociceptive nerves (“pain nerves”) in the synovial membrane (Table 2) (modified from ref.4).
Many of the substances mentioned above as being chondrocyte-produced, proinflammatory, and pain-provoking (algogenic) agents have been long recognized to be present in synovial fluid in pathophysiologically significant concentrations. However, due to the negligence of the potential role of chondrocytes as their perhaps true initial source, they have usually been considered to be derived from cells located in the synovial membrane. This, however, would be somewhat paradoxical considering the widely accepted dogma of OA as being primarily a disease of the articular cartilage, not of the synovial membrane. Therefore, it is possible to envision a sequence of events in which chondrocytes in the cartilage matrix, located in their lacunae, are subjected to stimuli that lead to chondrocytic inflammation, with consequences to the nearby synovial membrane. Later during the course of the disease, secondary inflammation in the synovial membrane might become more self-perpetuating.
The regulatory signals that stimulate the production of the above-mentioned chondrocyte-derived mediators, such as SP or NE, are not known. However, recent findings of Toll-like receptors (TLRs) in both chondrocytes [5] and progenitor cells [6] of the cartilage suggest that TLR ligands might form an important group of potential local chondrocyte stimulators. First, TLRs were recognized as pattern-recognizing receptors, binding and being stimulated by various pathogen-derived repeat structures called pathogen-associated molecular patterns (PAMPs). Lipopolysaccharide (endotoxin) from gram-negative bacteria and peptidoglycans from gram-positive bacteria are examples of such TLR-stimulating PAMPs.
Next, it was recognized that various endogenous structures released from necrotic cells can also act as TLR ligands. High mobility group box chromosomal protein 1 has already been implicated in the pathogenesis of OA [7] and heat-shock protein chaperones are further examples of such endogenous danger signals or alarmins (damage-associated molecular patterns). It has become clear that not only are alarmins passively (reactively) released by necrotic cells after loss of their plasma membrane integrity, but cells activated to inflammatory responses can also proactively release alarmins, as if preparing the inflammatory and immune cells for an eventual later-occurring full-scale inflammatory response.
Table 3 Finally, it was discovered that ligands derived from, for example, macromolecules of the cartilage ECM can also serve as ligands for TLRs, probably in particular molecules that are partially degraded and denatured, and therefore are “biomarkers” of tissue stress and damage (e.g., in degenerating or traumatized cartilage) [8–10] (Table 3). The local concentration of these ECM-derived alarmins is probably maintained and enhanced by their steric exclusion by the hyaluronan-based matrix of the cartilage and synovial fluid. ECM-derived chondrocyte stimulators deserve the acute major interest of scientists active in the field.
It can therefore be concluded that the avascular and aneural hyaline articular cartilage can produce substances that are able to cause pain and secondary synovial inflammation according to a mechanism that suggests that OA could be considered as an autoinflammatory disease. It could be initiated as a proinflammatory reaction against degradation products of cartilage ECM produced locally at high concentrations as a result of traumatic and degenerative degradation of cartilage, leading directly at their source to a reactive chondrocyte-mediated production of proinflammatory and algogenic secondary mediators, which then cause a secondary synovitis and pain.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article and revising it critically for important intellectual content, and all authors approved the final version to be published.
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