Basement membrane components in the chondrocyte extracellular matrix

Detta är en avhandling från Lund University, Faculty of Medicine

Sammanfattning: The extracellular matrix (ECM) is a network of macromolecules which, together with cells, forms the various tissues of all metazoan organisms. Cartilage, in contrast to most other tissues, contains relatively few cells in proportion to the volume occupied by ECM. Part of this work involves investigation of cartilage ECM for expression and secretion of proteins that are considered to be the defining components of a specialized ECM known as a basement membrane (BM). We show that indeed all the four defining components of BMs, laminins, type IV collagen, perlecan and nidogens are expressed in cartilage. Furthermore, we show that these proteins localise to the chondrcyte pericellular matrix, where we suggest they form the functional equivalent of a basement membrane. Perlecan, as stated previously, is one of the cardinal components of BMs. Fibulin, another protein found both in basement membranes and cartilage, has previously been found to be involved in organization of the cartilage ECM. A further aim of this work was therefore to investigate any role that perlecan plays in cartilage ECM organization. we show that a specific glycosilation variant of perlecan potently stimulates collagen fibril formation. We further show that stimulation can be accomplished by the specific Chondroitin sulfate (CS) chain of perlecan, independently of the core protein. Investigation of the CS chain composition reveals that it is enriched in a specific high sulfation disaccharide (CS-E) and we postulate that this high sulfation CS-chain is necessary for collagen fibril formation stimulation. We also continue to investigate the mechanism by which stimulation is accomplished and show that stimulation is accomplished through a non-crossbridging mechanism that cannot be inhibited by an excess of non-stimulatory glycosaminoglycan. Heparin, which shares biological characteristics with the high sulfation CS-E, also stimulates fibril formation. The efficacy of heparin is however significantly higher and further differences include the ability of heparin fragments as small as heptamers to stimulate fibril formation while CS-E fragments appear to lose their stimulatory traits upon even partial digestion. In conclusion we show that basement membrane components are present in cartilage ECM and that they may serve roles both as BM functional equivalents as well as organizational roles during ECM formation.

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