Aggrecan modulation of growth plate morphogenesis

Departments of Pediatrics and Biochemistry and Molecular Biology, Committee on Developmental Biology, The University of Chicago, Chicago, IL 60637, USA.
Developmental Biology (Impact Factor: 3.55). 04/2009; 329(2):242-57. DOI: 10.1016/j.ydbio.2009.02.024
Source: PubMed


Chick and mouse embryos with heritable deficiencies of aggrecan exhibit severe dwarfism and premature death, demonstrating the essential involvement of aggrecan in development. The aggrecan-deficient nanomelic (nm) chick mutant E12 fully formed growth plate (GP) is devoid of matrix and exhibits markedly altered cytoarchitecture, proliferative capacity, and degree of cell death. While differentiation of chondroblasts to pre-hypertrophic chondrocytes (IHH expression) is normal up to E6, the extended periosteum expression pattern of PTCH (a downstream effector of IHH) indicates altered propagation of IHH signaling, as well as accelerated down-regulation of FGFR3 expression, decreased BrdU incorporation and higher levels of ERK phosphorylation, all indicating early effects on FGF signaling. By E7 reduced IHH expression and premature expression of COL10A1 foreshadow the acceleration of hypertrophy observed at E12. By E8, exacerbated co-expression of IHH and COL10A1 lead to delayed separation and establishment of the two GPs in each element. By E9, increased numbers of cells express P-SMAD1/5/8, indicating altered BMP signaling. These results indicate that the IHH, FGF and BMP signaling pathways are altered from the very beginning of GP formation in the absence of aggrecan, thereby inducing premature hypertrophic chondrocyte maturation, leading to the nanomelic long bone growth disorder.

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    • "Versican is transiently expressed in the undifferentiated mesenchymal cells of the early limb bud, during the onset of prechondrogenic condensation, and in developing joints (Bode-Lesniewska et al., 1996; Choocheep et al., 2010; Schwartz and Domowicz, 2002; Shepard et al., 2007; Snow et al., 2005). Mice lacking Aggrecan die at birth and are dwarfed (Domowicz et al., 2009; Watanabe et al., 1994) whereas conditional removal of Versican or HA in the limb mesoderm leads to focal joint defects (Choocheep et al., 2010; Matsumoto et al., 2009; McDonald and Camenisch, 2002). Thus, these studies show a direct role for ECM proteoglycans in joint establishment and development. "
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    ABSTRACT: Joint and skeletal development is highly regulated by extracellular matrix (ECM) proteoglycans, of which chondroitin sulfate proteoglycans (CSPGs) are a major class. Despite the requirement of joint CSPGs for skeletal flexibility and structure, relatively little is understood regarding their role in establishing joint positioning or in modulating signaling and cell behavior during joint formation. Chondroitin sulfate synthase 1 (Chsy1) is one of a family of enzymes that catalyze the extension of chondroitin and dermatan sulfate glycosaminoglycans. Recently, human syndromic brachydactylies have been described to have loss-of-function mutations at the CHSY1 locus. In concordance with these observations, we demonstrate that mice lacking Chsy1, though viable, display chondrodysplasia and decreased bone density. Notably, Chsy1(-/-) mice show a profound limb patterning defect in which orthogonally shifted ectopic joints form in the distal digits. Associated with the digit-patterning defect is a shift in cell orientation and an imbalance in chondroitin sulfation. Our results place Chsy1 as an essential regulator of joint patterning and provide a mouse model of human brachydactylies caused by mutations in CHSY1.
    Full-text · Article · Mar 2012 · Developmental Biology
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    • "Extracellular matrix proteins produced by chondrocytes have also exhibited a capacity to regulate growth plate chondrocyte hypertrophy. Thus, type II collagen, aggrecan, and matrilin-3 are likely to inhibit hypertrophy as these matrix component deficiency produced premature maturation in mutant chondrocytes [140] [141] [142]. Furthermore a functional link between chondrocyte hypertrophy and extracellular matrix degradation is also supported by the fact that downregulation of chondrocyte hypertrophy evidenced by suppression of type X collagen, Runx2 and MMP-13 expression is associated with inhibition of collagen cleavage activity in cultured hypertrophic growth plate chondrocytes treated with MMP-13 inhibitor [8] [143] [144]. "
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    Full-text · Article · Jan 2011
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    • "Recently, Cortes et al. have shown that the brachymorphic (bm) mouse defective in sulfation of chondroitin sulfate proteoglycans shows defects in Ihh signaling and gradient formation in the developing growth plate (Cortes et al. 2009). Further experimental data showed that Ihh binds to the major cartilage chondroitin sulfate proteoglycan (CSPG) aggrecan via its CS chains (Domowicz et al. 2009). These data suggest that HSPGs and CSPGs function in concert to establish an Ihh morphogen gradient in the epiphyseal growth plate, suggesting another level of complexity to understanding how proteoglycans regulate morphogen gradients in various developmental contexts. "
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    ABSTRACT: During development, secreted morphogens such as Wnt, Hedgehog (Hh), and BMP emit from their producing cells in a morphogenetic field, and specify different cell fates in a direct concentration-dependent manner. Understanding how morphogens form their concentration gradients to pattern tissues has been a central issue in developmental biology. Various experimental studies from Drosophila have led to several models to explain the formation of morphogen gradients. Over the past decade, one of the main findings in this field is the characterization of heparan sulfate proteoglycan (HSPG) as an essential regulator for morphogen gradient formation. Genetic and cell biological studies have showed that HSPGs can regulate morphogen activities at various steps including control of morphogen movement, signaling, and intracellular trafficking. Here, we review these data, highlighting recent findings that reveal mechanistic roles of HSPGs in controlling morphogen gradient formation.
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