Defects in extracellular matrix structural proteins in the osteochondrodysplasias

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Daniel H. Cohn

Medical Genetics, Steven Spielberg Pediatric Research Center, Ahmanson Department of Pediatrics, Cedars-Sinai Medical Center, and Departments of Human Genetics and Pediatrics, UCLA School of Medicine, Pos Angeles, CA 90048, USA

A bstract. Mutations in the genes that encode structural proteins of the extracellular matrix affect one or more steps in the diverse set of coordinated events necessary for ordered skeletal development. Depending on the role of the gene product and the severity of the defect, disruption of endochondral ossification and linear growth, the structural integrity and stability of articular cartilage, and/or mineralization can occur. Several themes have emerged from the molecular dissection of these disorders; most of the osteochondrodysplasias that result from defects in structural proteins are inherited in an autosomal dominant fashion; a spectrum of related clinical phenotypes can be produced by distinct mutations in the same gene; haploinsufficiency for the gene product usually produces a milder clinical phenotype than do mutations resulting in synthesis of structurally abnormal proteins. For structural defects, a dominant-negative effect resulting from presence of the abnormal protein in the matrix appears to be the primary determinant ofphenotype. Secondary effects on extracellular matrix protein structure can result from defects in post-translational maturation, including hydroxylation, sulfation and proteolytic cleavage, and produce distinct osteochondrodysplasias. Overall, the inherited disorders of skeletogenesis have revealed the exquisite sensitivity of the architecture of the extracellular matrix to the quantity and quality of matrix molecules.

2001 The molecular basis of skeletogenesis. Wiley, Chichester (Novartis Foundation Symposium 232)p 195-212

The last decade has witnessed an explosion in our understanding of the molecular basis of human osteochondrodysplasias (Mundlos & Olsen 1997a,b). The identities of the osteochondrodysplasia disease genes reflect the diverse set of coordinated events necessary for ordered skeletal development. Depending on the specific gene product involved, the molecular defects disrupt one or more steps in skeletogenesis, including (a) effects on mesenchymal condensation and establishment of the size and shape of the cartilaginous skeletal primordia; (b) disarray in the growth plate with consequent defects in endochondral ossification and linear growth; (c) degradation of the structural integrity and stability of articular cartilage leading to degenerative processes in the joints; and (d) disrupted mineralization and bone (re)modelling.

Many of the osteochondrodysplasia disease genes encode structural proteins of the extracellular matrix. Despite the expression of these proteins early in skeletal development, establishment of the cartilage anlagen in most of these disorders proceeds normally. More commonly, defects in the structural proteins of the matrix disrupt the ordered process of differentiation, proliferation, hypertrophy and mineralization at the growth plate. These alterations lead to disordered linear growth and often produce deformity in addition to short stature. For articular cartilage, a structurally altered cartilage extracellular matrix is inherently unstable and is subject to degradation, leading to early onset degenerative joint disease and osteoarthritis. This is the major cause of morbidity in these conditions and is particularly evident in the main weight bearing joints, the hips and knees. Not surprisingly, the need for joint replacement is a common consequence in many osteochondrodysplasias.

The most recent classification of this clinically and genetically heterogeneous group of disorders recognizes over 150 distinct osteochondrodysplasia phenotypes (International Working Group on the Constitutional Diseases of Bone 1998). The classification is primarily radiographic, with the different disorders divided on the basis of the specific skeletal elements that are affected and the severity of the defect. The characterization of the disease genes in many of these conditions is leading to an emerging molecular classification, separate but parallel to the clinical and radiographic nosology, that is useful in defining the conditions in biomolecular terms.

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