Undersulfated chondroitin sulfate in the cartilage matrix of brachymorphic mice

Orkin, Roslyn W.; Pratt, Robert M.; Martin, George R.

doi:10.1016/0012-1606(76)90069-5

Cited by 138 publications

(40 citation statements)

References 37 publications

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“…These studies further show that brachymorphic cartilage contains undersulfated chondroitin sulfate (21). The ultrastructural studies reported here support the biochemical findings and indicate that the majority of the proteoglycans in brachymorphic cartilage are visualized as a network of thin filaments associated with collagen (see reference 20), rather than being in the form of polygonal matrix granules.…”

Section: Orkin Williams Cranley Oppke and Bi~own Cartilage Of Brasupporting

confidence: 84%

Defects in the cartilaginous growth plates of brachymorphic mice.

Orkin¹,

Williams²,

Cranley³

et al. 1977

The Journal of Cell Biology

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Homozygous brachymorphic (bm/bm) mice are characterized by disproportionately short stature. Newborn bm/bm epiphyseal cartilages are shorter than normal although the cells in the different zones of growth are relatively well organized. The extracellular matrix reacts poorly with stains specific for sulfated glycosaminoglycans. The ultrastructural appearance of the cartilage matrix indicates normal collagen fibrils; however, proteoglycan aggregate granules are smaller than normal and are present in reduced numbers, particularly in the columnar and hypertrophic zones of the growth plate. In addition, a prominent network of fine filaments, which are extractable in 4 M guanidine hydrochloride, are present in the bm/bm cartilage matrix. These findings suggest that a defect affecting the proteoglycan component of cartilage occurs in bm/bm mice.Numerous inherited disorders affect cartilage structure and function in man and other animals. Recently, we have studied cartilage from brachymorphic (bm/bm) mice. This mutant was first described by Lane and Dickie (12), and established by genetic studies as an autosomal recessive condition. Homozygous bm/brn mice are vigorous but have shortened long bones, shortened tails, and dome-shaped skulls. Such findings are consistent with a defect in cartilage development, and Lane and Dickie found the knee joints of 17-24 day old bin~bin mice to be shorter and thicker than normal, although chondrocytes in these epiphyseal growth plates retained good alignment (12).Cartilage is composed predominantly of one cell type, chondrocytes, surrounded by large quantities of extracellular matrix. Of the constituents of the extracellular matrix, two macromolecules, cartilage-type collagen (19, 36) and cartilage-specific proteoglycans (13,22), are synthesized by the differentiated chondrocytes. Ultrastructurally, this extracellular matrix consists of thin, 200-300 ,~ wide cartilage-type collagen fibrils and polygonal matrix granules of precipitated proteoglycan aggregates (1,6,18,25,(33)(34)(35).In examining the cartilaginous epiphyses from bm/bm mice, we have observed alterations in the morphological appearance of the epiphyseal growth plates at different stages of development, as well as differences in the extracellular matrix material which may be related to the abnormalities in tissue development found in this mutant.

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Section: Orkin Williams Cranley Oppke and Bi~own Cartilage Of Brasupporting

confidence: 84%

Defects in the cartilaginous growth plates of brachymorphic mice.

Orkin¹,

Williams²,

Cranley³

et al. 1977

The Journal of Cell Biology

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“…The pathology in human spondyloepimetaphyseal dysplasia is considered to be similar to that found in the brachymorphic mouse, i.e. undersulphation of extracellular matrix proteoglycan [22]. We believe that this apparent enigma has now been resolved by the demonstration that, in the cartilaginous growth plate of guinea-pig long bones, PAPS synthase 2 is, indeed, the predominant isoform being expressed, whereas PAPS synthase 1 is poorly expressed.…”

Section: Discussionmentioning

confidence: 84%

Characterization and expression of human bifunctional 3′-phosphoadenosine 5′-phosphosulphate synthase isoforms

Fuda

Shimizu

Lee

et al. 2002

Biochemical Journal

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Sulphonation, a fundamental process essential for normal growth and development, requires the sulphonate donor molecule 3h-phosphoadenosine 5h-phosphosulphate (PAPS), which is produced from ATP and inorganic sulphate by the bifunctional enzyme PAPS synthase. In humans, two genes encode isoenzymes that are 77 % identical at the amino acid level, and alternative splicing creates two subtypes of PAPS synthase 2. The question as to whether distinctions in amino acid composition are reflected in differences in activity has been examined. The specific activity of the PAPS synthase 2 subtypes is 10-to 15-fold higher than that for PAPS synthase 1. The greater catalytic efficiency of the PAPS synthase 2 subtypes is demonstrated further by the 3-to 6-fold higher k cat \K m ratios for ATP and inorganic sulphate as compared with the ratios for PAPS synthase 1. In humans, PAPS synthase 1 is expressed ubiquitously, and is the dominant isoform in most tissues, whereas expression of the PAPS synthase 2

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“…To elucidate the importance of CS in endochondral bone formation, we are taking advantage of the brachymorphic (bm) mouse (Sugahara and Schwartz, 1979;Sugahara and Schwartz, 1982a;Sugahara and Schwartz, 1982b). The bm mouse has a mutation in the gene Papss2, which encodes PAPS synthetase 2 (PAPSS2), one of two isoforms in mammals that catalyze the synthesis of the universal sulfate donor PAPS (Kurima et al, 1998), thus resulting in severe undersulfation of CSPGs (Orkin et al, 1976). The bm mouse is characterized by a dome-shaped skull, short thick tail and shortened limbs (Lane and Dickie, 1968;Schwartz and Domowicz, 2002;Schwartz et al, 1978).…”

Section: Sulfation Of Chondroitin Sulfate Proteoglycans Is Necessary mentioning

confidence: 99%

Sulfation of chondroitin sulfate proteoglycans is necessary for proper Indian hedgehog signaling in the developing growth plate

2009

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In contrast to the functional role of heparan sulfate proteoglycans (HSPGs), the importance of chondroitin sulfate proteoglycans (CSPGs) in modulating signaling pathways involving hedgehog proteins, wingless-related proteins and fibroblast growth factors remains unclear. To elucidate the importance of sulfated CSPGs in signaling paradigms required for endochondral bone formation, the brachymorphic (bm) mouse was used as a model for undersulfated CSPGs. The bm mouse exhibits a postnatal chondrodysplasia caused by a mutation in the phosphoadenosine phosphosulfate (PAPS) synthetase (Papss2) gene, leading to reduced levels of PAPS and undersulfated proteoglycans. Biochemical analysis of the glycosaminoglycan (GAG) content in bm cartilage via sulfate labeling and fluorophore-assisted carbohydrate electrophoresis revealed preferential undersulfation of chondroitin chains (CS) and normal sulfation of heparan sulfate chains. In situ hybridization and immunohistochemical analysis of bm limb growth plates showed diminished Indian hedgehog (Ihh) signaling and abnormal Ihh protein distribution in the extracellular matrix. Consistent with the decrease in hedgehog signaling, BrdU incorporation exhibited a significant reduction in chondrocyte proliferation. Direct measurements of Ihh binding to defined GAG chains demonstrated that Ihh interacts with CS, particularly chondroitin-4-sulfate. Furthermore, co-immunoprecipitation experiments showed that Ihh binds to the major cartilage CSPG aggrecan via its CS chains. Overall, this study demonstrates an important function for CSPGs in modulating Ihh signaling in the developing growth plate, and highlights the importance of carbohydrate sulfation in regulating growth factor signaling.

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Undersulfated chondroitin sulfate in the cartilage matrix of brachymorphic mice

Cited by 138 publications

References 37 publications

Defects in the cartilaginous growth plates of brachymorphic mice.

Defects in the cartilaginous growth plates of brachymorphic mice.

Characterization and expression of human bifunctional 3′-phosphoadenosine 5′-phosphosulphate synthase isoforms

Sulfation of chondroitin sulfate proteoglycans is necessary for proper Indian hedgehog signaling in the developing growth plate

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