OSTEOARTHRITIS: The breakdown of Cartilage: Chondrocytes and the Cartilage Matrix
Healthy joints normally have little or no inflammation, and maintain a functional and strong cartilage matrix including healthy cartilage cells (chondrocytes) in the matrix. Chondrocytes are critical in the production and maintenance of the cartilage matrix. The matrix is composed primarily of collagen and proteoglycans. There is an important homeostatic balance between the production of the cartilage matrix and the wearing down of the matrix at the joint, from normal wear and tear. Insufficient maintenance of the cartilage matrix creates a situation where the b the wearing down of the matrix, and elimination of the cartilage.
Inflammation is the Key Activator in Articular Cartilage Destruction. Inflammation which affects cartilage may have different sources of origin. Osteoarthritis inflammation can form at an injury in the joint tissue, either in cartilage matrix itself, or adjacent structures. Cartilage destruction is the result of pro-inflammatory cytokines, which attack both the cartilage matrix producing cells (chondrocytes) as well as the cartilage matrix itself.
An important inflammatory cytokine in osteoarthritis is Interleukin 1beta (IL-1beta). IL-1beta is responsible for the breakdown of articular cartilage, and is a causative factor in osteoarthritis. Specifically, IL-1 beta:
• Causes cellular death of articular chondrocytes.
• Activates matrix degrading enzymes (aggrecanase, MMPs)
• Decreases expression of matrix components
Two matrix degrading enzymes are upregulated during inflammatory states of the joint. These enzymes are aggrecanases and MMPs:
(1) Aggrecanases – which breakdown the aggregcan cartilage component and is the PRIMARY ENZYME involved in cartilage breakdown Aggrecan is a significant part of cartilage, consisting of large proteolglycans. ADMA 1 and ADMA 2 are the key agrecanase enzymes affecting articular cartilage. Aggrecanese activity is involved in early cartilage degradation, and are the PRIMARY ENZYMES involved with aggrecan and cartilage destruction THE INHIBITION OF AGGRECANESE CAN PREVENT CARTILAGE DEGRADTION. The MMP enzyme plays more of a secondary role, and activates collagen and aggrecan degradation well after the process has been initiated by aggrecanese,(1) The inhibition of aggrecanese activity is a potential therapeutic target in arthritis treatment. In a genetically modified mouse model, whereby the aggregan enzyme gene was deleted, cartilage degradation was prevented.(2)
(2) Matrix Metalloproteinases (MMPs), are secondarily responsible for cartilage degradation and specifically affects the type II collagen component of cartilage (with less significant aggrecan breakdown activity). Inflammation increases the gene expression of MMPs in the joint area, which eat away and destroy the cartilage matrix. MMP enzyme activity is initiated subsequent to aggrencanese beginning the destruction of the cartilage.
Curcumin: Support for Healthy Cartilage | Cartilage Cells | Cartilage Breakdown Inhibitor CURCUMIN XTRA-MAX
• Curcumin protects joints against cartilage damage by inflammatory IL-1beta. The IL-1beta inflammatory cytokine is among the most destructive inflammatory cytokine to the joint and articular cartilage. Studies have shown that curcumin provides significant protection against the devastating effects of IL-1beta. Including: protection of chondrocytes, inhibiting expression of matrix degrading enzymes (aggrecanase, MMP), and blocking the degradation of critical cartilage matrix components proteolglycans and collagen type II. (3)
• Curcumin promotes chondrogenic (new cartilage cell formation) in a zone within the articular cartilage. Normally, damaged cartilage is incapable of repair or stimulating new cartilage cells. However, a specific area of articular cartilage, known as the superficial zone, contains progenitor chondrocyte cells which may be stimulated, when inflammation has been blocked. High levels of inflammation are pervasive in injured joints and damaged cartilage. Curcumin sufficiently blocks the inflammation in the articular zone to promote new chondrocyte differentiation.(4) Researchers concluded that curcumin may be capable of facilitating chrondrogenesis (new cartilage cell development) in living tissue, by reversing the effects of the inflammatory cytokines in the area of the articular cartilage. Further stating that “this strategy may support the regeneration of articular cartilage”.
• Curcumin and Quercetin both inhibit expression of aggrecanase enzymes. Gene expression of the matrix degrading enzyme aggrecanese was suppressed not only during the administration time period, but also for a period of 10-15 days after post-treatment, when quercetin and curcumin has been already been stopped.(5)
• Curcumin Reduces Leptin levels (the adipokine “hormone” from fat cells). Leptin increases MMP expression, a major family of enzymes responsible for the breakdown of the extracellular matrix of cartilage. (6) Since curcumin lowers leptin levels, it may also influence leptin mediated increases in MMP levels.
• Curcumin may prevent intervertebral disc degeneration. Intervertebral discs are the fibrocartilage discs which lie between adjacent vertebrae in the spine. Like other cartilage, the fibrocartilage disc requires constant maintenance of the cartilage matrix. Chonrdrocytes and collagen II gene expression provide the material for disc maintenance, ensuring that the disc remains strong and healthy. NF-kappaB , an inflammatory transcription factor, can inhibit the gene expression necessary for cartilage maintenance, resulting in degeneration of the disc. Suppression of cartilage forming gene expression is the most significant biological change observed with disc degeneration Curcumin is an inhibitor of NF-kappaB, and thereby allowing for the activation of gene expression for disc cartilage building (7).
Luteolin and Apigenin: Inhibiting the breakdown of the Matrix
• Luteolin inhibits the activities of the cartilage destroying aggrecanese enzymes. However, with respect to MMP enzymes, luteolin did not block the activity of this second group of enzymes.(8)
• Apigenin, on the otherhand, showed strong inhibition of aggrecanese, hyluronidase and MMP enzymes. In one study, apigenin was shown to also inhibit the breakdown and release of aggrecan and hyaluronic acid from the extracellular cartilage matrix. Hyulronic acid is a non-proteoglycan component of the cartilage extracellular matrix, and is important for resisting compression of the joint. In this instance apigenin acted as both an inihibitor of aggecanese and hyluronidase, preventing breakdown of two important components of the cartilage extracellular matrix.(9)
• In a second study, Apigenin also demonstrated inhibition of induction of the MMP-13 enzyme, by inflammatory cytokine stimulation.(10)