Three generations of a nonconsanguineous family with premature onset of primary (idiopathic) osteoarthritis (OA) were studied for clues to the etiopathogenesis of their disorder. Articular symptoms began in their second and third decades of life and involved multiple joints, both typical and atypical for primary OA. Radiographs of the majority of involved peripheral joints showed abnormalities typical of primary OA. Evidence of chondrodysplasia was found in the spines. Pathologic examination of femoral heads obtained at total hip arthroplasty from 3 affected family members showed moderate to severe OA. Articular cartilage proteoglycans from these specimens were evaluated for aggregatability with hyaluronic acid, levels of chondroitin sulfate and keratan sulfate, and core protein structure. The results from each patient's specimen differed from the results of the other specimens. We conclude that this family's disorder, primary OA associated with a mild chondrodysplasia, was a late-onset overlap form of an epiphyseal dysplasia, that a defect common to hyaline articular and physeal cartilage was primary, and that a single structural proteoglycan abnormality was not likely to be the underlying cause.

Early-onset primary osteoarthritis and mild chondrodysplasia. Radiographic and pathologic studies with an analysis of cartilage proteoglycans.

Patients with pseudoachondroplasia have a skeletal dysplasia with marked short stature. The most common cause of this condition is an autosomal dominant mutation, although autosomal recessive inheritance has been reported. Linkage to 2 cartilage-specific candidate genes, type II collagen (COL2A1) and proteoglycan link protein genes (CRTL1), was tested in 9 autosomal dominant families with pseudoachondroplasia. Tight linkage to these candidate genes was excluded with LOD scores for COL2A1 of −2.45 at θ= 0.05 and for CRTL1 of −7.28 at θ= 0.001. Discordant inheritance of the disease phenotype with each of these genes was also observed. Thus, these 2 candidate genes can be excluded as the cause of disease in these families. © Wiley-Liss, Inc.

Exclusion of human proteoglycan link protein (CRTL1) and type II collagen (COL2A1) genes in pseudoachondroplasia

Vitamin A and its congeners, collectively called retinoids, are known to have teratogenic potential and have induced craniofacial and limb malformations in numerous animal species. More importantly, retinoids are recognized as teratogenic to fetuses of pregnant women who have taken such preparations for dermatologic disorders. Information gathered from the study of animal models suggests that retinoids interfere with cartilage differentiation. If chondrogenesis in limb development is disturbed it may contribute to limb reductions and malformations. In vitro studies using various animal systems have shown that cartilage matrix macromolecules are altered to resemble those secreted by mesenchymal cells. The response of human chondrocytes to retinoids in vitro is not known. Culture of human chondrocytes in agarose maintains the cartilage phenotype and therefore serves as a model system to evaluate the influence of retinoids directly on human chondrogenesis. The studies presented in this paper were done to determine if the expression of specific matrix macromolecules of human chondrocytes in agarose culture is altered by retinol treatment. Immunocytochemistry demonstrated enhanced labeling of type I collagen while type II collagen labeling was reduced in cultures treated with retinol. In addition, morphometric analyses indicated a decrease in the size and number of chondrogenic clusters and that individual cells synthesized less alcian blue matrix when compared to parallel control cultures. The size of the proteoglycan monomers, glycosaminoglycan side chains as well as the disaccharide composition were not affected. However, there was a reduction in the quantity of proteoglycan monomers produced.

J. Spranger

Papers

Newly synthesized proteoglycans in pseudoachondroplasia