The extracellular matrix of the intervertebral disc structures contains many molecules also found in cartilage. The extremely polyanionic proteoglycans play a central role, particularly in the nucleus, by creating an osmotic environment leading to retention of water and ensuing resistance to deformation-important for the resilience of the tissue. Another major structural entity particularly important in the anulus is the network of collagen fibers; fibril-forming collagen 1 is a major constituent. The collagen fibrils in the anulus are largely oriented in sheets around the nucleus. A number of molecules present in the matrix regulate and direct the collagen fibril assembly by interacting with the collagen molecule and also the formed fibril. Several of these molecules bind by one domain to the collagen fiber and present another functional domain to interact either with other fibers or with other matrix constituents. In this manner the collagen fibers are cross-linked into a network that provides tensile strength and distributes load over large parts of the anulus. Diminished function in these cross-bridging molecules will lead to loss of mechanical properties of the collagen network and result in an impaired ability of the anulus to resist forces delivered by compression of the disc and particularly the nucleus. A different network abundant in the disc and in other load-bearing tissues is based on the beaded filaments of collagen 6. The basic building block is a tetramer of two pairs of antiparallel collagen-6 molecules arranged such that two N-terminal ends of collagen 6 are exposed at either end of the unit. Further assembly occurs both by end-to-end and side-to-side associations. This process is catalyzed by both biglycan and decorin, where the combined effect of direct binding of the core protein to the collagen-6 N-terminal globular domain and the presence of the glycosaminoglycan side chain is essential. These ligands are bound at the same site in complexes extracted from the tissue and then also have one bound molecule of matrilin-1, 2, or 3, in turn bound to a collagen fiber, a procollagen molecule, or an aggrecan. Interactions at the cell surface provide signals to the cells with regard to the conditions of the matrix. Such interactions include binding by matrix components to various receptors at the cell surface. Remodeling of the matrix takes place in response to various factors. An early event in disease is degradation of aggrecan by the members of the ADAMTS (a disintegrin-like and metalloprotease with thrombospondin motifs) family and degradation of molecules important in maintaining the collagen network.
Hormone-sensitive lipase (HSL), a key enzyme in fatty acid mobilization in adipocytes, has been demonstrated also in skeletal muscle. To gain further insight into the role and importance of HSL in skeletal muscle, a transcriptome analysis of soleus muscle of HSL-null mice was performed. A total of 161 transcripts were found to be differentially expressed. Increased mRNA levels of fructose-1,6-bisphosphatase, fructose-2,6-bisphosphatase, and phosphorylase kinase ␥ 1A suggest a higher glycogen flux in soleus muscle of HSLnull mice. An observed increase in the utilization of glycogen stores supports this finding. Moreover, an increased amount of intramyocellular lipid droplets, observed by transmission electron microscopy, suggests decreased mobilization of lipid stores in HSL-null mice. To complement the transcriptome data, protein expression analysis was performed. Five spots were found to be differentially expressed: pyruvate dehydrogenase E1 ␣ , creatine kinase (CK), ankyrin-repeat domain 2, glyceraldehyde-3-phosphate dehydrogenase, and one protein yet to be identified. The increased protein level of CK indicates creatine phosphate degradation to be of increased importance in HSL-null mice. The results of this study suggest that in the absence of HSL, a metabolic switch from reliance on lipid to carbohydrate energy substrates takes place, supporting an important role of HSL in soleus muscle lipid metabolism. The two major energy substrates found in skeletal muscle, carbohydrate and fat, are stored as glycogen and triglycerides, respectively. It is well established that during high-intensity exercise, creatine phosphate degradation and glycogen breakdown are the major energy-yielding pathways. During prolonged submaximal exercise, oxidative metabolism becomes the predominant mechanism for the muscle cell to produce ATP (1). Available fuels for oxidative metabolism include muscle glycogen, blood glucose, and NEFA. The relative reliance on these substrates is mainly determined by exercise intensity and duration. NEFA could originate either from circulating lipids or through hydrolysis of intramyocellular triglyceride stores.In the early 1960s, Randle and coworkers (2, 3) proposed a mechanism for the coordinated control of the utilization of glucose and fatty acids and also demonstrated a mechanism for the perturbation of carbohydrate metabolism by increased fat oxidation in muscle known as the glucose-fatty acid cycle or the Randle cycle. Since then, studies have shown that increased plasma NEFA availability results in a reduction in muscle carbohydrate oxidation and glycogen utilization (4, 5). Other studies have examined the effect of reduced plasma NEFA availability on carbohydrate metabolism by administration of nicotinic acid, which decreases plasma NEFA by inhibiting lipolysis in adipose tissue (6-8). These studies have shown that a reduction of plasma NEFA availability promotes an increase in carbohydrate oxidation during exercise. An increased activation of pyruvate dehydrogenase (PDH), possibly r...
Degradation of bovine nasal cartilage induced by interleukin-1 (IL-1) was used to study catabolic events in the tissue over 16 days. Culture medium was fractionated by two-dimensional electrophoresis (isoelectric focusing and SDS-PAGE). Identification of components by peptide mass fingerprinting revealed released fragments representing the NC4 domain of the type IX collagen ␣1 chain at days 12 and 16. A novel peptide antibody against a near N-terminal epitope of the NC4 domain confirmed the finding and indicated the presence of one of the fragments already at day 9. Mass spectrometric analysis of the two most abundant fragments revealed that the smallest one contained almost the entire NC4 domain cleaved between arginine 258 and isoleucine 259 in the sequence -ETCNELPAR 258 -COOH NH 2 -ITP-. A larger fragment contained the NC4 domain and the major part of the COL3 domain with a cleavage site between glycine 400 and threonine 401 in COL3 (-RGPPGPPGPPGPSG 400 -COOH NH 2 -TIG-). The presence of multiple collagen ␣1 (IX) N-terminal sequences demonstrates that the released molecules were cleaved at sites very close to the original N terminus either prior to or due to IL-1 treatment. Matrix metalloproteinase 13 (MMP-13) is active and cleaves fibromodulin in the time interval studied. Cartilage explants treated with MMP-13 were shown to release collagen ␣1 (IX) fragments with the same sizes and with the same cleavage sites as those obtained upon IL-1 treatment. These data describe cleavage by an MMP-13 activity toward non-collagenous and triple helix domains. These potentially important degradation events precede the major loss of type II collagen.In hyaline cartilage type IX collagen is a minor constituent of the fiber network, and type II collagen is the major constituent. The type IX collagen molecule (1) is a heterotrimer consisting of polypeptide chains ␣1, ␣2, and ␣3 (2). It belongs to the fibrilassociated collagens with interrupted triple helix. Each chain contains three triple helical (collagenous) domains, COL1, 2 -2, and -3, surrounded by four non-triple helical (non-collagenous) domains, NC1, -2, -3, and -4 ( Fig. 1) (3). The domain numbers are counted from the C terminus. Using electron microscopy, it has been shown that type IX collagen decorates the surface of type II collagen fibrils and that the NC4 domain forms a globular structure, which together with the stalklike COL3 domain protrudes out from the type II collagen fibril (4). Type IX collagen is covalently cross-linked to the type II collagen fibrils through binding to both type II collagen and other type IX collagen molecules (5-7). These bonds render extraction of type IX collagen from mature cartilage virtually impossible by agents that do not cleave peptide bonds. The NC4 domain has been shown to have an affinity for a number of molecules, for example heparin and cartilage oligomeric matrix protein (8 -10), whereas the COL domains interact with matrilin-3 (11).Mutations in the interactive cartilage oligomeric matrix protein MATN-3 and COL9 have ...
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