skeletal PTHrP development

Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 05/2006; 1068(1):1-13. DOI: 10.1196/annals.1346.002
Source: PubMed


Parathyroid hormone-related protein (PTHrP) participates in the regulation of endochondral bone development. After the cartilage mold is established in fetal life, perichondrial cells and chondrocytes at the ends of the mold synthesize PTHrP. This ligand then acts on PTH/PTHrP receptors on chondrocytes. As chondrocytes go through a program of proliferation and then further differentiation into post-mitotic, hypertrophic chondrocytes, PTHrP action keeps chondrocytes proliferating and delays their further differentiation. Indian hedgehog (Ihh) is synthesized by chondrocytes that have just stopped proliferating and is required for synthesis of PTHrP. The feedback loop between PTHrP and Ihh serves to regulate the pace of chondrocyte differentiation and the sites at which perichondrial cells first differentiate into osteoblasts. Activation of the PTH/PTHrP receptor leads to stimulation of both Gs and Gq family heterotrimeric G proteins. Genetic analyses demonstrate that Gs activation mediates the action of PTHrP to keep chondrocytes proliferating, while Gq activation opposes this action. Downstream from Gs activation, synthesis of the cyclin-cdk inhibitor, p57, is suppressed, thereby increasing the pool of proliferating chondrocytes. PTHrP's actions to delay chondrocyte differentiation are mediated by the phosphorylation of the transcription factor, SOX9, and by suppression of synthesis of mRNA encoding the transcription factor, Runx2. These pathways and undoubtedly others cooperate to regulate the pace of differentiation of growth plate chondrocytes in response to PTHrP.

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    • "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.
    Preview · Article · Sep 2014 · Biochemical and Biophysical Research Communications
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    • "Other targets downstream of Ga s , which are likely involved in Ga s -regulated chondrocyte differentiation, include the suppression of the cyclin–CDK inhibitor p57; the PKA-dependent phosphorylation and activation of the transcription factor SOX9; and the suppression of the transcription of RUNX2, probably as a consequence of suppression of MEF2C action (reviewed by Kronenberg (2006)). "
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    ABSTRACT: Here we reviewed regulation of differentiation of the growth plate chondrocytes by G-proteins. In connection with this we summarized the current knowledge regarding each family of G-protein alpha subunit, specifically, Gαs, Gαq/11, Gα12/13 and Gαi/o. We discussed different mechanisms involved in chondrocyte differentiation downstream of G-proteins and different g-protein coupled receptors (GPCRs) activating G-proteins in the epiphyseal chondrocytes. We concluded that among all G-proteins and GPCRs expressed by chondrocytes, Gαs has the most important role and prevents premature chondrocyte differentiation. Receptor for parathyroid hormone (PTHR1) appears to be the major activator of Gαs in chondrocytes and ablation of either one leads to accelerated chondrocyte differentiation, premature fusion of the postnatal growth plate and ultimately short stature.
    Full-text · Article · Jun 2014 · Journal of Molecular Endocrinology
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    • "A line of evidence provided by genetically altered mouse models has revealed that Ihh increases the expression of parathyroid hormone-related protein (PTHrP) in perichondrial cells and chondrocytes at the ends of long bones, which delays chondrocyte hypertrophy through the PTH/PTHrP receptor expressed in proliferating chondrocytes. Thus, Ihh and PTHrP function in a local negative feedback loop to regulate the onset of hypertrophic differentiation (40). In addition, it is also reported that Ihh stimulates the proliferation and maturation of chondrocytes independently of PTHrP, in which activation of Wnt and bone morphogenetic protein (BMP) signaling is suggested to be involved (41,42,43). "
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    ABSTRACT: Endochondral bone formation involves multiple steps, consisting of the condensation of undifferentiated mesenchymal cells, proliferation and hypertrophic differentiation of chondrocytes, and then mineralization. To date, various factors including transcription factors, soluble mediators, extracellular matrices (ECMs), and cell-cell and cell-matrix interactions have been identified to regulate this sequential, complex process. Moreover, recent studies have revealed that epigenetic and microRNA-mediated mechanisms also play roles in chondrogenesis. Defects in the regulators for the development of growth plate cartilage often cause skeletal dysplasias and growth failure. In this review article, I will describe the current understanding concerning the regulatory mechanisms underlying chondrogenesis.
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