Osteoarthritis (OA) is a chronic degenerative disorder which occurs when the cartilage that cushions the ends of bones in joints wear down over a period of time. The molecular mechanisms of osteoarthritis have not received much attention among the public, except the few who are in research and development of drugs. OA is the most prevalent chronic joint disease, which increases in prevalence with age and affects majority of persons over 65.
Unlike Rheumatoid arthritis (RA), OA is caused by mechanical wear and tear at the joints. Also, while RA can occur at any stage, OA occurs later in life of the individual. Both however, share some similarities in their symptoms. But, while RA affects both sides of the affected joints, OA can affect one side of the joint.
Symptoms of Osteoarthritis
Symptoms of Osteoarthritis may develop slowly and worsen over a period of time. Some of the signs and symptoms include:
• Loss of flexibility at the affected joints.
• Pain at the affected joint.
• Stiffness of joints especially upon awaking.
• Tenderness of tissues around the affected joints.
Pathological Progression of Osteoarthritis
The pathological process of osteoarthritis begins by an alteration in the composition and organization of the extracellular matrix. When this happens, the articular chondrocytes exhibit a transient proliferative response and increased matrix synthesis (Col2, aggrecan etc) in an attempt to initiate repair of damage caused by pathological stimulation.
Changes in the composition and structure of the cartilage further stimulate chondrocytes to produce more catabolic factors involved in cartilage degradation. As a result, the proteoglycans and collagen network break down, leading to the disruption of the cartilage integrity. Later on, the chondrocytes will undergo apoptosis and the articular cartilage will be completely lost. The molecular mechanisms of osteoarthritis involve several pathways that network with each other to induce inflammatory response in osteoarthritis patients and include growth factors and cytokines.
Growth Factors and Osteoarthritis
Transforming growth factor B (TGF-B) plays important role in skeletogenesis and inhibits chondrocyte hypertrophy and maturation. The inhibition of TGF-B represents a potential mechanism in the development of OA, and the loss of TGF-B is associated with cartilage damage. Some other growth factors that play important roles in cartilage homeostasis are fibroblast growth factor-2 and 18 (FGF-2 and FGF-18). FGF-2 has a potent catabolic and anti-anabolic role in human cartilage homeostasis. It is released in supraphysiological amounts during loading/ injury of the cartilage matrix. It activates multiple transduction signal pathways (MAPKs) such as ERK, p38 and JNK. FGF-2 can stimulate MMP-13 expression, which is the major degrading enzyme to type II collagen. Its stimulation also mediates the up-regulation of matrix-dependent enzyme expression (ADAMTS-5 and MMP-13) and the down-regulation aggrecan expression. But PKCგ inhibition significantly impairs the detrimental effects mediated by FGF-2.
FGF-18 which is a secreted heparin-binding polypeptide growth factor is involved in cartilage growth and maturation and is implicated in the development of functional cartilage and bone tissue. It has roles in enhancing regeneration and repression of damaged cartilage by stimulating chondrogenesis.
Molecular Mechanism of Wnt/β-catenin Signaling in Osteoarthritis
Wnts are a family of extracellularly secreted glycoproteins that are in numerous biological activities, including cell proliferation, differentiation, polarization and fate determination. They have been implicated in the development of some diseases through canonical β-catenin-dependent and noncanonical β catenin-dependent signaling pathways.
During cartilage development, Wnt/β-catenin signaling activity is strictly regulated in chondrogenesis and chondrocyte maturation. Excessive Wnt pathway activation in the adult articular cartilage under IL-1β stimulation is thought to be an OA progression susceptibility factor. An increase in expression of Wnt1 pathway activator, Wnt inducible-signaling pathway protein 1 (WISP-1) induces articular cartilage degradation through up-regulation of the expression MMPs and aggrecanases in chondrocytes and macrophages. But the expression levels of some wnt pathway antagonists, such as sclerostin, dickkopf WNT signaling pathway inhibitor 1 (DKK1), and secreted frizzled-related protein 3 (sFRP3) usually decreases in parallel with OA progression. Therefore, an up-regulation of the expression of these antagonists alleviates OA cartilage destruction. A mutant in sFRP3 causes increased levels of active β-catenin, thereby promoting abnormal articular chondrocyte hypertrophy and results in hip and knee in OA patients.
Molecular Mechanism of the PI3K/AkT/mTOR Pathway in OA Pathogenesis
The PI3/AkT/mTOR pathway plays significant roles in the molecular mechanisms of osteoarthritis in three aspects of OA which are cartilage, synovial inflammation and subchondral bone sclerosis.
Cartilage homeostasis is important to articular health and is defined as the state in which synthesis of extracellular matrix (ECM) is balanced by its degradation. The destruction of cartilage homeostasis initiates and boosts OA pathogenesis. It is marked by elevated MMPs, a disintegrin and metalloproteinases with thrombospondrin motifs (ADAMTSs) and a reduced collagen II and aggrecan levels.
The PI3K/AkT pathway plays a role in both ECM anabolism and catabolism. When stimulated, AkT promotes the synthesis of collagen II and an over-expression of AkT enhances proteoglycan synthesis in human chondrocytes under the stimulation of tert-butylhydroperoxide (tBHP). When PI3k is activated, Akt is phosphorylated, which promotes the activation of mTORC1. The activated mTORC1 inhibits autophagy by associating with ULK1- Atg13-FIR200 complex, thereby inhibiting autophagosome formation. Inhibiting of mTOR and the subsequent increase in autophagic activity may restore homeostasis in articular cartilage chondrocytes.
NF-kB in OA Pathogenesis
When excessively activated, NF-kB signaling up-regulates hypoxia-inducible factor 2α (HIF-2α) transcription. This results in enhanced OA progression through further induction of catabolic factors such as MMPs, VEGF and IHH. But a moderate activity of NF-kB is required to maintain healthy articular cartilage.
The NF-kB-HIF-2α axis may be a potential therapeutic target. This is because a moderate dose of an IKK inhibitor can suppress HIF-2α expression without significant effect on cell survival.
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