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The role of aggrecan in embryonic growth plate cytoarchitecture and differentiation: a rescue model (344.6)
Author(s) -
Lauing Kristen,
Cortes Mauricio,
Domowicz Miriam,
Henry Judith,
Schwartz Nancy
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.344.6
Subject(s) - aggrecan , chondrocyte , biology , microbiology and biotechnology , cartilage , sox9 , perichondrium , endochondral ossification , growth factor , extracellular matrix , proteoglycan , fibroblast growth factor , anatomy , transcription factor , genetics , pathology , osteoarthritis , gene , medicine , alternative medicine , receptor , articular cartilage
The homozygous cmd mouse harbors a mutation resulting in the complete absence of the proteoglycan aggrecan in the extracellular matrix of growth plate cartilage. In this study, we examine specifically how this proteoglycan influences the cytoarchitecture and differentiation of chondrocytes within growth plate zones. We utilize the cmd mouse (cmd/cmd) and a novel transgenic mouse expressing chick aggrecan driven by the Col2a1 promoter (tg/+) to elucidate the role of this proteoglycan on chondrocyte survival and proliferation, as well as growth factor production and chondrocyte transcription factor expression. E18.5 cmd embryos display a 55% decrease in limb length, aberrant spatial and temporal mRNA expression patterns of chondrocyte growth factors, and a significant increase in cell death levels in chondrocytes adjacent to the perichondrium compared to wild type controls. Expression of the novel transgene in “rescue” embryos (cmd/cmd::tg/+) results in a 20% increase in limb element length compared to cmd mutant embryos. In situ hybridization demonstrates a partial restoration of normal growth factor and transcription factor gene expression patterns for Indian hedgehog, Patched, Collagen X, FGFR3, and Sox9 compared to cmd growth plates. In addition, the growth plates of rescue embryos display improved chondrocyte morphology and matrix production, particularly within the proliferative and hypertrophic zones. Notably, rescue growth plates display significantly decreased cell death levels compared to cmd embryos in the perichondrial region while concomitantly increasing proliferation levels in the growth plate. The results of this study suggest that aggrecan influences the temporal and spatial patterns of growth factor production by chondrocytes in the embryonic growth plate, and is essential to chondrocyte organization, morphology, and survival during embryonic limb growth. Grant Funding Source : Supported by the National Institutes of Child Health and Human Development (R01 HD017332)