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Notch signaling components are upregulated during both endochondral and intramembranous bone regeneration.

ABSTRACT: Previous studies have demonstrated that Notch signaling regulates endochondral and intramembranous bone formation by controlling cell proliferation and differentiation. Notch signaling has also been shown to regulate healing in a variety of tissues. The objective of this study was to characterize and compare activation of the Notch signaling pathway during endochondral and intramembranous bone healing using tibial fracture and calvarial defect injury models, respectively. Bilateral tibial fractures or bilateral 1.5 mm diameter calvarial defects were created in mice, and tissues were harvested at 0, 5, 10, and 20 days post-fracture. Gene expression of Notch signaling components was upregulated during both tibial fracture and calvarial defect healing, with expression generally higher during tibial fracture healing. The most highly expressed ligand and receptor during healing, Jag1 and Notch2 (specifically the activated receptor, known as NICD2), were similarly localized in mesenchymal cells during both modes of healing, with expression decreasing during chondrogenesis, but remaining present in osteoblasts at all stages of maturity. Results suggest that in addition to embryological bone development, Notch signaling regulates both endochondral and intramembranous bone healing.

SUBMITTER: Dishowitz MI

PROVIDER: S-EPMC3210892 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Notch signaling components are upregulated during both endochondral and intramembranous bone regeneration.

Dishowitz Michael I MI Terkhorn Shawn P SP Bostic Sandra A SA Hankenson Kurt D KD

Journal of orthopaedic research : official publication of the Orthopaedic Research Society 20110804 2

Previous studies have demonstrated that Notch signaling regulates endochondral and intramembranous bone formation by controlling cell proliferation and differentiation. Notch signaling has also been shown to regulate healing in a variety of tissues. The objective of this study was to characterize and compare activation of the Notch signaling pathway during endochondral and intramembranous bone healing using tibial fracture and calvarial defect injury models, respectively. Bilateral tibial fractu ...[more]

PMID: 21818769

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Project description:Enhanced understanding of differential gene expression and biological pathways associated with distinct phases of intramembranous bone regeneration following femoral marrow ablation surgery will improve future advancements regarding osseointegration of joint replacement implants, biomaterials design, and bone tissue engineering. A rat femoral marrow ablation model was performed and genome-wide microarray data were obtained from samples at 1, 3, 5, 7, 10, 14, 28, and 56 days post-ablation, with intact bones serving as controls at Day 0. Bayesian model-based clustering produced eight distinct groups amongst 9,062 significant gene probe sets based on similar temporal expression profiles, which were further categorized into three major temporal classes of increased, variable, and decreased expression. Differential biological processes and pathways associated with each major temporal group were identified, and significantly expressed genes involved were visually represented by heat maps. It was determined that the increased expression group exclusively contains genes involved in pathways for matrix metalloproteinases (MMPs), Wnt signaling, TGF-Î² signaling, and inflammatory pathway. Only the variable expression group contains genes associated with glycolysis and gluconeogenesis, Notch Signaling Pathway, natural killer cell mediated cytotoxicity, and B cell receptor signaling pathway, among others. The decreased group exclusively consists of genes involved in heme biosynthesis, p53 signaling pathway, and hematopoietic cell lineage. Significant biological pathways and transcription factors expressed at each time point post-ablation were also identified. These data present the first temporal gene expression profiling analysis of the rat genome during intramembranous bone regeneration induced by femoral marrow ablation. In an Institutional Animal Care and Use Committee (IACUC) approved study, 27 adult male rats (Sprague Dawley, 400-425 g) were divided into nine groups: intact control (0 day), and 1, 3, 5, 7, 10, 14, 28, and 56 days post marrow ablation. Twenty-four animals received unilateral femoral ablation. At each time point, animals were killed in a carbon dioxide chamber, and whole femurs were harvested and denuded of soft tissue. For three samples per time point, both the distal and proximal ends of the femurs were cut off in order to exclude the epiphyses and growth plate regions. Diaphyseal marrow tissue and cells from the mid-shaft were flushed out using TrizolÂ®. Extracted RNA was homoginized and was prepared for hybridization. For each of the three samples per time point, gene expression was analyzed with GeneChipÂ® Rat Genome 230 2.0 Arrays (Affymetrix, Santa Clara, CA).

Dataset Information

Notch signaling components are upregulated during both endochondral and intramembranous bone regeneration.

Publications

Notch signaling components are upregulated during both endochondral and intramembranous bone regeneration.

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