Transcriptional networks controlling chondrocyte proliferation and differentiation during endochondral ossification

Department of Developmental Biology, Center for Medical Biotechnology, University Duisburg-Essen, 45117 Essen, Germany.
Pediatric Nephrology (Impact Factor: 2.86). 12/2009; 25(4):625-31. DOI: 10.1007/s00467-009-1368-6
Source: PubMed


During endochondral ossification bones are formed as cartilage templates in which chondrocytes proliferate, differentiate into hypertrophic chondrocytes and are gradually replaced by bone. Postnatally, remnants of embryonic chondrocytes remain in a restricted domain between the ossified regions of the bones forming the growth plate. The coordinated proliferation and differentiation of chondrocytes ensures the continuous elongation of the epiphyseal growth plates. The sequential changes between proliferation and differentiation are tightly regulated by secreted growth factors, which activate chondrocyte-specific transcription factors. Transcription factors that play critical roles in regulating cell-type-specific gene expression include Sox9, Gli2/3, and Runx2. The interaction of these transcription factors with general transcriptional regulators like histone-modifying enzymes provides an additional level of regulation to fine-tune the expression of target genes in different chondrocyte populations. This review will outline recent advances in the analysis of the complex transcriptional network that regulates the distinct steps of chondrocyte differentiation.

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    • "This process begins with the condensation of mesenchymal cells forming cartilage anlagen, which outline the later bone structures. Within the cartilage anlagen chondrocytes undergo differentiation from proliferating to prehypertrophic and hypertrophic stages before they are eventually replaced by bone through the concerted action of osteoclasts and osteoblasts [1]. One of the key regulators of chondrocyte differentiation is the signaling molecule Indian hedgehog (Ihh). "
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    ABSTRACT: One of the key regulators of endochondral ossification is Indian hedgehog (Ihh), which acts as a long-range morphogen in the developing skeletal elements. Previous studies have shown that the distribution and signaling activity of Ihh is regulated by the concentration of the extracellular glucosaminoglycan heparan sulfate (HS). An essential step during biosynthesis of HS is the epimerization of D-glucuronic to L-iduronic acid by the enzyme glucuronyl C5-epimerase (Hsepi or Glce). Here we have investigated chondrocyte differentiation in Glce deficient mice and found increased regions of proliferating chondrocytes accompanied by a delayed onset of hypertrophic differentiation. In addition, we observed increased expression levels of the Ihh target genes Patched1 (Ptch1) and Parathyroid hormone related peptide (Pthrp; Pharathyroid hormone like hormone (Pthlh)) indicating elevated Ihh signaling. We further show that Ihh binds with reduced affinity to HS isolated from Glce(-/-) mice. Together our results strongly indicate that not only the level, but also the structure of HS is critical in regulating the distribution and signaling activity of Ihh in chondrocytes. Copyright © 2015. Published by Elsevier B.V.
    Matrix biology: journal of the International Society for Matrix Biology 06/2015; DOI:10.1016/j.matbio.2015.06.004 · 5.07 Impact Factor
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    • "apoptosis. The circulating IGF-1 and local Runx2 expression in the growth plate chondrocytes are known to promote chondrocyte differentiation into mature state, thereby inducing longitudinal bone growth [8] [27]. Furthermore, the upregulation of PTHrP expression in the RZ and HZ also represented an effort to increase chondrocyte proliferation in order to maintain cell number in the growth plate of GK rats [8] [10] [11]. "
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    ABSTRACT: Type 2 diabetes mellitus (T2DM) is much more detrimental to bone than previously thought. Specifically, it is associated with aberrant bone remodeling, defective bone microstructure, poor bone quality, and growth retardation. The T2DM-associated impairment of bone elongation may result from a decrease in growth plate function, but the detailed mechanism has been unknown. The present study, therefore, aimed to test hypothesis that T2DM led to premature apoptosis of growth plate chondrocytes in Goto-Kakizaki (GK) type 2 diabetic rats, and thus triggered the compensatory responses to overcome this premature apoptosis, such as overexpression of Runt-related transcription factor (Runx)-2 and vascular endothelial growth factor (VEGF), the essential mediators for bone elongation. The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) of epiphyseal sections successfully revealed increases in chondrocyte apoptosis in the hypertrophic zone (HZ) and chondro-osseous junction of GK rats. Quantitative immunohistochemical analysis further confirmed the overexpression of parathyroid hormone-related protein (PTHrP), Runx2 and VEGF, but not Indian hedgehog (Ihh) in the HZ. Analysis of blood chemistry indicated suppression of bone remodeling with a marked decrease in parathyroid hormone level. In conclusion, GK rats manifested a premature increase in chondrocyte apoptosis in the HZ of growth plate, and a compensatory overexpression of chondroregulatory proteins, such as PTHrP, Runx2, and VEGF. Our results, therefore, help explain how T2DM leads to impaired bone elongation and growth retardation.
    Biochemical and Biophysical Research Communications 09/2014; 452(3). DOI:10.1016/j.bbrc.2014.08.085 · 2.30 Impact Factor
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    • "In addition, in this age group, thyroid cartilages from male specimens were observed to contain a significantly higher percentage of apoptotic chondrocytes than did thyroid cartilages from women (Claassen et al., 2009). In accordance with the growth plate (Wuelling and Vortkamp, 2010; Mackie et al., 2011), death of chondrocytes by apoptosis is a prerequisite for endochondral ossification. Furthermore , we do not agree with some authors (Harrison and Denny, 1983; Garvin, 2008; Dang-Tran et al., 2010) reporting that although ossification increases with advancing age an immediate correlation with age is poor. "
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    ABSTRACT: Endochondral ossification is a process that also occurs in the skeleton of the larynx. Differences in the ossification mechanism in comparison to growth plates are not understood until now. To get deeper insights into this process, human thyroid cartilage was investigated by the use of X-rays and a series of light-microscopic stainings. A statistical analysis of mineralization was done by scanning areas of mineralized cartilage and of ossification. We detected a special mode of endochondral ossification which differs from the processes in growth plates. Thyroid cartilage ossifies very slowly and in a gender-specific manner. Compared with age-matched women, bone formation in thyroid cartilage of men is significantly higher in the age group 41-60 years. Endochondral ossification is prepared by internal changes of extracellular matrix leading to areas of asbestoid fibers with ingrowing cartilage canals. In contrast to growth plates, bone is deposited on large areas of mineralized cartilage, which appear at the rims of cartilage canals. Furthermore, primary parallel fibered bone was observed which was deposited on woven bone. The predominant bone type is cancellous bone with trabeculae, whereas compact bone with Haversian systems was seldom found. Trabeculae contain a great number of reversal and arresting lines meaning that the former were often reconstructed and that bone formation was arrested and resumed again with advancing age. It is hypothesized that throughout life trabeculae of ossified thyroid cartilage undergo adaptation to different loads due to the use of voice. Clin. Anat., 2014. (c) 2014 Wiley Periodicals, Inc.
    Clinical Anatomy 04/2014; DOI:10.1002/ca.22309 · 1.33 Impact Factor
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