Human cartilage does not have the capacity for parent-like regeneration; instead, following injury, there is a programmed attempt at regeneration that ultimately results in fibrocartilage formation. This lack of intrinsic repair has been attributed to the avascular state of the tissue and chondrocyte dedifferentiation towards a cell incapable of type II collagen production and with altered responsiveness to the structural and regulatory mediators within its microenvironment. For several decades, debate has existed regarding the role Transforming Growth Factor-Beta (TGF-P) plays in modulating articular cartilage. Blocking of TGF-p signaling in mice by a dominant negative type II TGF-p receptor and transgenic knockouts of Smad 3, a central mediator of TGF-p signaling, result in osteoarthritic-like phenotypes, whereas local up-regulation of TGF-p promotes cartilage healing in degenerative joint disease models. Despite TGF-p being implicated as a key player In the regulation of chondrocyte phenotype and extracellular matrix (ECM), little is known about TGF-p action in human chondrocytes. These investigations have established a critical link between variation in TGF-p receptor expression at the cell surface and TGF-p action in cartilage. In addition to the TGF-p signaling receptors, the presence of betaglycan and RIIB (a spliced variant of the type II signaling receptor) was confirmed on human chondrocytes. Moreover, the expression of three novel TGF-p receptors was identified, namely Sol RI (a soluble form of the type I receptor), Alk-l, and endoglin. These receptors formed a variety of heteromeric complexes and regulated TGF-p signaling. More importantly, RIIB and endoglin were demonstrated to regulate type II collagen levels and evidence was provided that they likely represent chondrocyte phenotypic markers. A critical link between endoglin expression, cell phenotype, TGF-~ responsiveness, and ECM was established. These results demonstrate the formation of TGF-~ receptor heteromeric complexes of various subtype composition on chondrocytes suggesting that such complexes may regulate TGF-~ signaling pathways in those cells. Cell surface TGF-~ binding proteins, acting as phenotypic markers in human cartilage, are potential modulators of complex interactions between the cell and its microenvironment. Therefore, novel TGF-~ receptors may provide an avenue to regulate the effects ofTGF-~ locally and establish new insights into cartilage regeneration or repair.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.19424 |
| Date | January 2003 |
| Creators | Parker, Wendy Lynne |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Surgical Research) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002010032, Theses scanned by McGill Library. |
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