Pathophysiology of osteoarthritis
Osteoarthritis (OA) is a multifactorial disease characterized by a progressive degeneration and eventual failure of the synovial joint functionality. Although it has been traditionally considered as an exclusive disease of the articular cartilage, nowadays it is considered as a whole joint disease....
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2017 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/456376 |
| Acceso en línea: | http://hdl.handle.net/10803/456376 |
| Access Level: | acceso abierto |
| Palabra clave: | Artrosi Artrosis Osteoarthritis Fisiologia patològica Fisiología patológica Pathological physiology Ciències Experimentals i Matemàtiques 575 |
| Sumario: | Osteoarthritis (OA) is a multifactorial disease characterized by a progressive degeneration and eventual failure of the synovial joint functionality. Although it has been traditionally considered as an exclusive disease of the articular cartilage, nowadays it is considered as a whole joint disease. Therefore, the progression of the disease involves articular cartilage degeneration, osteochondral bone sclerosis and synovial membrane hypertrophy. Articular cartilage is a connective tissue resistant to tensile and shears strength that is composed of water (>70%) and a dense extracellular matrix (ECM) that encompasses the unique cellular type of the cartilage, the chondrocytes. The major component of the ECM is the collagen network consisting mainly of type II collagen fibers and type IX and XI collagen macromolecules attached to the surface of the fiber. Non-collagenous components such as GAGs, aggregated proteoglycans (mainly aggrecan) and small leucine rich proteoglycans (SLRP’s) are also binding the collagen fiber. Cartilage is a no innervated and also an avascular tissue, thus gets its nutrients by diffusion from the synovial fluid. Due to this condition, chondrocytes live in a hypoxic environment, and intracellular survival factors, such as hypoxia-inducible factor 1α, are required for maintenance of homeostasis and adaptation to the mechanical environment. Under physiological conditions, the collagen network and proteoglycan content is maintained by the chondrocytes. However, local and systemic risk factors could lead chondrocytes to fail to maintain the ECM and thus the cartilage tissue is progressively degraded. To this point, the three general objectives of this thesis are: 1. Collagenase-3 (COL3) also known as MMP13, is a matrix metalloproteinase abnormally over-expressed in pathological processes. Several COL3 transcripts are expressed in human chondrocytes although their role in OA is still unknown. This study aimed to characterize the presence of two non-canonical COL3 isoforms, named COL3-DEL (deleted form) and COL3-9B (exon 9 added form) in human OA cartilage, and to analyse their proteolytic activity. 2. Opticin (OPTC), a SLRP known to play a role in the assembly of the fibrillar collagens and the structural stability of the extracellular matrix, was previously demonstrated to be produced and degraded in osteoarthritic (OA) human cartilage. Here, we further investigated the OPTC role in OA cartilage by the study of the in vivo effect of OPTC deficiency in mouse model 3. Chondroitin sulfate (CS) is a Symptomatic Slow acting Drug against Osteoarthritis (SySADOA) with anti-inflammatory effects. In this study, we tried to unveil the mechanism of action on osteoarthritic synovial membrane. The general discussion of this thesis is: OA is a heterogeneous disease that encloses multiple phenotypes. In order to develop new diagnostic and prognostic tools and eventually advance in the discovery of successful treatments, clearly defining the different phenotypes of OA is of great importance. In this line, the findings comprised in this thesis reveal two different approaches to identify patient’s subgroups. On one hand, and as described in chapter 1, the presence of a new discovered collagenase-3 (COL3) isoform (COL3-DEL) resulting from a mutation of the canonical COL3, could be used as an indicator of differential extracellular matrix degradation in human articular cartilage. On the other hand, results from chapter 2 suggest that the compositions of the members of SLRP super-family in the human extracellular matrix of the articular cartilage could be applied as a new tool for OA prognosis classification. Finally, the controversy regarding the efficacy of systemic treatment with nutraceuticals – including chondroitin sulfate - may arrive to an end if new tools are used to predict which patients are best suited for a given drug. Importantly, further work remains to be done to understand how to integrate these findings into a final and comprehensive concept that could explain the patient’s heterogeneity and the differential prognosis of OA disease. |
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