Osteoarthritis pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohammadmain Rezazadehsaatlou [2].
Overview
Pathophysiology
Osteoarthritis (OA) is a well-known degenerative joint disease influencing millions of peopleworldwide. Osteoarthritis count as a complex disease caused by changes in the tissue homeostasis of articular cartilages and subchondral bones. The cell/extra-cellular matrix (ECM) and their interactions play an important role in the pathophysiology of articular cartilage and the occurrence of Osteoarthritis; consequently, the main feature of OA is that after this process in involved joint the articular cartilages of involved joint no longer have a normal acting system and for example because of the the extracellular matrix destruction this articular cartilages cannot act as a shock absorber. Different pathogenic mechanisms have been proposed to be responsible for the occurrence of OA. Heredity, obesity, hypoxia, synovitis–capsulitissubchondral bone overload, joint instability (mechanical integrity disturbances) are the most important underlying causes in this regard. In the current pathogenesis of osteoarthritis (OA) all joint tissues including cartilage, bone, synovium, ligamentous capsular structures, and surrounding muscle are involved. OA characterized by structural changes such as: active bone remodeling, synovial inflammation, and articular cartilage degradation leading to the loss of joint function and angular deformity or malalignment. Also, a variety of bio markers in synovial fluid helped to create more clear insight about the biological response of joints to injury but no biomarker have been declared to be reliable for monitoring the development, progression, and response to therapy of OA. Its been reported that certain factors can increase the risk of the OA development such as: hereditary elements, trauma and mechanical stress, joint injury, age, obesity, physical activity, bone mineral density (BMD), congenital anomalies. and, during the last years signaling pathways mad a lot of attention and its been proven that these pathways play important rolls in inflammation in the remodeling subchondral bone, synovium, enzyme activation, and extracellular matrix degradation in articular cartilage.
Subchondral Bone
OA leads to the sub-chondral bone remodeling. This event is often along with the sub-chondral cysts formation as a result of focal resorption. OA can alter chondrocyte metabolism in Bony cells. Osteoarthritis influencing whole joint system including both articular cartilage and underlying bone structures. One of the most common findings in is the subchondral bone plate thickening. The diseased bone becomes brittle and sclerotic; and the frequent turnovers affect bone quality. There is still a big question about this fact that does the subchondral bone changes happens simultaneously with the changes in articular cartilage or not. Articular overgrowths such as subchondral bone, leads to microtrauma, hardening, remodeling, and displacement of the osteochondral line and consequently, the energy-dissipation capacity and elasticity of the articular cartilage deceases. Macroscopic changes of the subchondral bone especially in load-bearing areas are: increased osteogenetic reactions, increased stiffness, increased density, and excessive formation of bone and cartilage (called osteochondrophytes). OA also is capable to influence the non–weight-bearing joints, such as: hands, spine, shoulders, and temporomandibular joints. The osteochondrophytes usually can be found in intra-articular, marginal, extraarticular, insertional, or enthesiophytes. The osteochondrophytes frequently involves the joint space, and with synovial metaplastic fragments or flaps of cartilage they lead to the articular ‘joint mice’ formation. On the other hand, the bone remodeling caused by: microfractures within the superficial bone trabeculae with the formation of subchondral bone cysts (known as erosive alterations). Bony changes such as sclerosis of the subchondral bone plate, alterations in trabecular structure, osteophytes and bone marrow lesions are associated with the initiation and progression of OA. It’s been reported that the subchondral bone changes prior to the articular cartilage changes. Meanwhile, it’s been found that the molecular pathways (for example: cytokines such as: IL-1, TNF-α, and fibrinolytic system including plasminogen, tissue plasminogen activators and urokinase plasminogen activators, and plasmin) have in subchondral play important roles in the disbalance between the physiological connection of bone deposition and remodelling and resorption potential. Higher osteoblastic activity results in an exaggerated reparative response, in contrast an increased osteoclastic degradative activity results in a predominantly erosive bony condition.
Articular Cartilage
The articular cartilage damage is one of the most important pathological causes of OA. But it is not clearly that whether if this pathological event originates from the cartilage or subchondral bone, loss and/or damage to articular cartilage or both of them are responsible for the development and progression of disease. Human articular cartilage system, acting as a shock absorber, consists of a hydrated extracellular matrix (as the functional element of the tissue) with few numbers of chondrocytes within. 70–80% of cartilage is consisted of water and collagens and proteoglycans are the major organic components. Collagen type II builds a network of fibers containing molecules within. Collagen type XI helps collagen type II in fibril network formation and also limiting the fiber diameter. Collagen type IX make crosslinks the whole collagen network. Heparan sulfate proteoglycans such as perlecan, have important role (such as interactions with heparin-binding growth factors like fibroblast growth factors, heparin binding forms of vascular endothelial growth factor (VEGF), and bone morphogenetic proteins (BMP)) in chondrogenesis. Higher demolition of heparan sulfate proteoglycans by glycosidases and matrix metalloproteinases are known to responsible for OA. Calcification and ossification in articular cartilage during OA and aging occurs due to the differentiation of chondrocytes. During the degenerative changes in involved joints calcification happens simultaneously with to increasing alkaline phosphates and pyrophosphate levels. Since the Articular cartilage has no internal vascular or lymphatic supply system so it is dependent on near tissues including subchondral bone and Synovial Membrane in receiving nutrients elements and excretion of products of made by articular matrix turnover and chondrocytic metabolism.
Synovial Membrane
The main task of Synovial Membrane is repairing any defects found in joint. The cellular compartment of Synovial Membrane of the SM is a major source of synovial fluid. These components are responsible for management of chondrocyte activities and maintaining the integrity of articular cartilage surfaces (using lubricin and hyaluronic acid molecules) in diarthrodial joints. After joint injury including trauma and/or OA the concentration of this molecular system changes. And during the progression of OA this synovial membrane changes into a main origin of proinflammatory and catabolic products such as metalloproteinases and aggrecanases. Thus, any damage to the Synovial Membrane can result in reducing of cartilage-protecting factors, and also increasing production of articular matrix degradation factors. A normal synovial membrane has fully control on the transmitted molecules in and out of the joint space. During some conditions such as trauma, inflammation, and OA this permeability of synovial membrane disrupts leading to reduced concentrations of lubricin and hyaluronic acid._and_complement_activation_(b)_in_the_joint_leading_to_synovitis_and_potentiation_of_cartilage_erosion_in_OA.jpg)
Joint Instability
Joint instability occurs due to the ligament laxity enhancement, poor muscles conditions, or ligament tearing or strain in a ligament or abnormal muscles status. Joint instability increases the incidence of OA. On the other hand, Joint instability could be found as a result of synovitis produces excessive amounts of synovial fluid.
Hypoxia
Neovascularization in synovial membrane, subchondral bone, and cartilage is a common finding in OA. Neovascularization in injured area increases the nutrients delivery of to the stressed articular cartilage and subchondral and also could cause the synovitis development in bone. Hypoxia as a common pathophysiological element of OA and rheumatoid arthritis because: during the OA, Cartilage thinning and cartilage erosion, ECM composition changes, and the cartilage fissures development are the most common findings in involved joint; these structural alteration influence the oxygen gradient near the articular cartilage. In OA and rheumatoid arthritis during the hypoxia two important angiogenic peptides including vascular endothelial growth factor and platelet-derived cellular endothelial growth factor increases due to the excessive expression of nuclear hypoxia-inducible factors. These angiogenic peptides increase local neovascularization and increase vascular permeability, and consequently cause inflammation, cartilage damage, edema, and protein vascular leak that worsen the joint involvement.