Fully mature collagen fibers are usually associated with the FACIT family of collagen molecules that reside on their surfaces. For example, type I fibrils are associated with type XII and type XIV collagens. These collagens contribute to the three-dimensional organization of fibers within the ECM. Type II collagen fibrils, which are abundant within the cartilage, are usually smaller in diameter than type I fibrils. However, these fibrils are also associated with type IX collagen (another member of the FACIT subgroup). Collagen type IX resides on the surface of the type II fibril and anchors it to proteoglycans and other components of the cartilaginous ECM (Fig. 6.11).
Collagen molecules are synthesized by various types of connective tissue and epithelial cells.
Collagen molecules are largely synthesized by connective tissue cells. These cells include fibroblasts in a variety of tissues (e.g., chondrocytes in cartilage, osteoblasts in bone, and pericytes in blood vessels). In addition, the collagen molecules of basement membrane (see page 139) are produced by epithelial cells. The synthesis of collagen is regulated by complex interactions among growth factors, hormones, and cytokines. For example, transforming growth factor (TGF-) and platelet-derived growth factor (PDGF) stimulate collagen synthesis by fibroblasts, whereas steroid hormones (glucocorticoids) inhibit its synthesis.
FIGURE 6.11 • Type II collagen fbril. This diagram illustrates the interaction between type II collagen fibrils and type IX collagen molecules in the cartilaginous matrix. Collagen type IX provides the link between the collagen fibrils and GAG molecules, which stabilizes the network of cartilage fibers.
Collagen fibers are degraded either by proteolytic or phagocytic pathways.
All proteins in the body are being continually degraded and resynthesized. These processes allow tissues to grow and to undergo remodeling. Initial fragmentation of insoluble collagen molecules occurs through mechanical wear, the action of free radicals, or proteinase cleavage. Further degradation is continued by specific enzymes called proteinases. The resulting colla gen fragments are then phagocytosed by cells and degraded by their lysosomal enzymes. Excessive collagen degradation is observed in several diseases (e.g., degradation of cartilage collagen in rheumatoid arthritis or bone collagen in osteoporosis). Secreted collagen molecules are degraded mainly by two different pathways:  Proteolytic degradation occurs outside the cells through the activity of enzymes called matrix metalloproteinases (MMPs). These enzymes are synthesized and secreted into the ECM by a variety of connective tissue cells (fibroblasts, chondrocytes, monocytes, neutrophils, and macrophages), some epithelial cells (keratinocytes in the epidermis), and cancer cells. The MMPs include collagenases (which degrade type I, II, III, and X collagens); gelatinases (which degrade most types of denatured collagens, laminin, fibronectin, and elastin); stromelysins (which degrade proteoglycans, fibronectin, and denatured collagens); matrilysins (which degrade type IV collagen and proteoglycans); membrane-type MMPs (which are produced by  cancer cells and have a potent pericellular fibrinolytic activity); and macrophage metalloelastases (which degrade elastin, type IV collagen, and laminin).
In general, triple-helical undenatured forms of collagen molecules are resistant to degradation by MMPs. In contrast, damaged or denatured collagen (gelatin) is degraded by many MMPs, with gelatinases playing the prominent role. MMP activity can be specifically inhibited by tissue inhibitors of metalloproteinases (TIMPs). Because