Patients with osteoarthritis (OA) may experience severe pain, loss of mobility, and decreased productivity, along with increased healthcare costs. The progression of OA is multifactorial and driven by defective joint biomechanics, biochemical cascades, and the cellular immune response to an inflammatory environment.
The body’s natural wound healing response also manifests in the osteoarthritic joint and is generating interest in how the immune response may influence disease progression.
The acute phase of wound healing is marked by a short-lived influx of neutrophils followed by macrophage infiltration and neovascularization. The final step includes remodeling the damaged tissue. While the synovial membrane can become vascularized, cartilage is an avascular tissue.
Understanding the role of cells and signaling in inflammation/wound healing and the immunological processes involved may provide insight into the progression of OA. Furthermore, these processes could reveal potential therapeutic targets to slow the rate of progression or improve inherent repair mechanisms.
| The role of the macrophage in wound healing |
Inflammation is typically the response of vascularized tissue to injury.
Changes in vascular flow and permeability allow the influx of neutrophils into the lesion for phagocytosis of microorganisms and foreign bodies.
Monocytes then migrate and differentiate into macrophages and affect the inflammatory microenvironment with the release of proteases, radical oxygen species and inflammatory cytokines and the recruitment of fibroblasts and vascular endothelial cells. This leads to the development of granulation tissue that is remodeled locally.
With persistent stimulation, macrophages will continue to trigger inflammatory signaling. The progression of OA may, in fact, be driven by chronic inflammation in an attempt to repair damaged tissue.
M1 macrophages, once activated, trigger pro-inflammatory signaling to create a microbial cleansing and removal effect before remodeling can occur. M2 macrophages are associated with repair by releasing growth and angiogenic factors and regulating T cell function, promoting remodeling of damaged tissue.
The presence of complex macrophage phenotypes, particularly in the synovial membrane, could influence the progression of OA. The infiltration and activation of macrophages and lymphocytes in chronic synovitis produces the release of IL-1 and TNF-α, which, in turn, stimulates the production by chondrocytes of enzymes that degrade the matrix.
Likewise, the release of matrix degradation products into the synovial fluid triggers cellular feedback, further stimulating the production of catabolic enzymes. This produces a continuous catabolic stimulus in the macrophages, and therefore they do not transition to a remodeling phenotype because they continue to receive the "cleanup" signal.
By signaling digestive proteases, chondrocytes are released from the matrix and attempt to populate the injured site. However, in the middle and deep areas of the cartilage, this repair is too slow and the cell density is too low to overcome the ongoing degradation process.
Thus, synovial macrophages never receive an adequate signal to completely stop the inflammatory clearance process and continue the cycle of production of matrix-degrading proteases. In addition to inhibiting endogenous repair, chondrocyte senescence increases with age and contributes to disease progression by preventing repair.
Therefore, the progression of OA involves cross-reactions between the cells, tissues and synovial fluid present in the joint.
Many pathological processes result in altered or incomplete polarization of macrophages to a healing phenotype. This polarization is driven by the microenvironment and cytokine signaling; indeed, M1 polarization plays a critical role in the early stages of remodeling. Macrophage polarization could play a role in the control and even progression of OA.
| Innate immunity |
Activation of the innate immune system occurs when surface-expressed pattern recognition receptors (RRPs) bind to pathogen-associated molecular patterns (PMAP) and damage-associated molecular patterns (DMP). There are many classes of RRPs including Toll-like receptors (TLR), RIG-1-like receptors (RLR), and NOD-like receptors (NLR).
These receptors can activate nuclear transcription factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK), which, in turn, induce genes that encode enzymes and cytokines that cause cartilage catabolism through positive regulation of IL-1β and TNF-α.
Once activated, the cells and proteases of the innate immune system will carry out their task indiscriminately without taking into account whether the attack is directed at a contaminant or at the organism itself.
Activation of the complement cascade can improve the immune system by causing cell lysis, improving phagocytosis of neutrophils and macrophages, increasing vascular permeability and vasodilation, increasing leukotriene synthesis, and promoting chemotaxis of neutrophils and monocytes.
Complement components have been found in significant quantities in synovial fluid in OA. Formation of the membrane attack complex (MAC) was also identified in osteoarthritic cartilage, further illustrating the important role of complement in osteoarthritic progression. The complement could reach the synovial fluid by filtration from the blood; Synovial tissue cells can also produce complement.
The role of the innate immune system is to nonspecifically identify invaders, whether microbes or tissue fragments, and then activate to stimulate the elimination of unwanted material. In the case of OA, continued degradation will expose RRPs in the cartilage, perpetuating immune activation.
| adaptive immune system |
The adaptive immune system includes antibodies that bind to antigens; antibody-producing B lymphocytes (B cells); and T lymphocytes (T cells) that coordinate the elimination of pathogens. T cells are classified into helper T cells (Th cells) and cytotoxic T cells (Tc cells).
Th (CD4+) cells, which divide into Th1, Th2 and Th17, secrete cytokines to stimulate the proliferation and differentiation of cells involved in the immune response. Effector Tc (CD8+) cells eliminate target cells. The adaptive immune system is designed for the identification and elimination of intra- and extracellular microbes, and its regulation through Th cells may also influence the progression of OA.
Th2 cells can influence macrophage polarization. Through the release of cytokines, they guide macrophages to pro-regenerative phenotypes in response to tissue-derived biomaterials in an IL-4-dependent manner, evidencing that the Th cell has an important biological role in the control of inflammation and the repair.
There is evidence that T and B cells are present in greater numbers in organs with OA than in healthy controls. Catabolic cytokines produced from these cell types include IL-2, IFN-γ, and TNF-α.
| Conclusion |
The understanding of OA has evolved beyond considering it as a result of simple mechanical wear and tear in the joint. Fully understanding the mechanisms of these processes may lead to therapeutic targets to modulate OA progression.
