Abstract
Hox genes encode transcription factors, which regulate skeletal patterning and chondrocyte differentiation during the development of cartilage, the precursor to mature bone. Overexpression of the homeobox transcription factors Hoxc8 and Hoxd4 causes severe cartilage defects due to delay in cartilage maturation. Matrix metalloproteinases (MMPs), bone morphogenetic proteins (BMPs) and fibroblastic growth factors (FGFs) are known to play important roles in skeletal development and endochondral bone formation and remodeling. In order to investigate whether these molecules are aberrantly expressed in Hoxc8- and/or Hoxd4-transgenic cartilage, we performed quantitative RT-PCR on chondrocytes from Hox-transgenic mice. Gene expression levels of Bmp4, Fgf8, Fgf10, Mmp9, Mmp13, Nos3, Timp3, Wnt3a and Wnt5a were altered in Hoxc8-transgenic chondrocytes, and Fgfr3, Ihh, Mmp8, and Wnt3a expression levels were altered in Hoxd4-transgenic chondrocytes, respectively. Notably, Wnt3a expression was elevated in Hoxc8- and reduced in Hoxd4-transgenic cartilage. These results suggest that both transcription factors affect cartilage maturation through different molecular mechanisms, and provide the basis for future studies into the role of these genes and possible interactions in pathogenesis of cartilage defects in Hoxc8- and Hoxd4-transgenic mice.
Highlights
Hox genes encode transcription factors that are involved in patterning the individual elements of the developing skeleton during the development of cartilage, the precursor to mature bone
Using a binary transgenic system [2], we have previously shown that overexpression of the homeobox transcription factors Hoxc8 and Hoxd4 results in severe cartilage defects [3,4], characterized by delayed maturation, reduced proteoglycan content, accumulation of immature chondrocytes and decreased maturation to hypertrophy
In order to determine whether expression of genes in the chondrocyte differentiation and maturation pathways was altered in Hoxc8- or Hoxd4-transgenic mice, we assayed the prevalence of transcripts for genes known to participate in regulation of the chondrocyte differentiation pathway
Summary
Hox genes encode transcription factors that are involved in patterning the individual elements of the developing skeleton during the development of cartilage, the precursor to mature bone. Studies on animals provide evidence that patterning, growth and differentiation of skeletal elements are affected by mutations in Hox genes. Using a binary transgenic system [2], we have previously shown that overexpression of the homeobox transcription factors Hoxc and Hoxd results in severe cartilage defects [3,4], characterized by delayed maturation, reduced proteoglycan content, accumulation of immature chondrocytes and decreased maturation to hypertrophy. Vertebral and rib cartilages contain accumulation of proliferating chondrocytes, indicating that cartilage maturation is affected by overexpression of Hoxc and Hoxd, respectively. The cartilage of the ribs is weak and structurally insufficient, resulting in pulmonary failure and perinatal death [3,4]
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