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: 4.31). 05/2006; 1068(1):1-13. DOI: 10.1196/annals.1346.002
Source: PubMed

ABSTRACT 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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    • "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.
    Journal of Molecular Endocrinology 06/2014; 53(2). DOI:10.1530/JME-14-0093 · 3.62 Impact Factor
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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.
    Clinical Pediatric Endocrinology 01/2014; 23(1):1-8. DOI:10.1292/cpe.23.1
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    • "This is based on our observations in the Cartigf-1r conditional knockouts, where we found decreased type II collagen and Ihh expression, but increased expression of PTHrP, potentially explaining the growth plate defects in these animals (Wang et al., 2011). The PTHrP/Ihh feedback loop is an autocrine/paracrine pathway (reviewed in Kronenberg, 2006)) that regulates the rate of chondrocyte differentiation (Vortkamp et al., 1996; Karp et al., 2000). In this model, PTHrP is produced by perichondrial and reserve (resting) cells in the embryonic skeleton and diffuses into the proliferation zone to activate PTHR1 in proliferating chondrocytes, thereby sustaining their proliferation and in effect, delaying their maturation (Lee et al., 1995; Chung et al., 1998). "
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    ABSTRACT: This review focuses on the anabolic effects of IGF-1 signaling on the skeleton, emphasizing the requirement for IGF-1 signaling in normal bone formation and remodeling. We first discuss the genomic context, splicing variants, and species conservation of the IGF-1 locus. The modulation of IGF-1 action by growth hormone (GH) is then reviewed while also discussing the current model which takes into account the GH-independent actions of IGF-1. Next, the skeletal phenotypes of IGF-1-deficient animals are described in both embryonic and postnatal stages of development, which include severe dwarfism and an undermineralized skeleton. We then highlight two mechanisms by which IGF-1 exerts its anabolic action on the skeleton. Firstly, the role of IGF-1 signaling in the modulation of anabolic effects of parathyroid hormone (PTH) on bone will be discussed, presenting in vitro and in vivo studies that establish this concept and the proposed underlying molecular mechanisms involving Indian hedgehog (Ihh) and the ephrins. Secondly, the crosstalk of IGF-1 signaling with mechanosensing pathways will be discussed, beginning with the observation that animals subjected to skeletal unloading by hindlimb elevation are unable to mitigate cessation of bone growth despite infusion with IGF-1 and the failure of IGF-1 to activate its receptor in bone marrow stromal cell cultures from unloaded bone. Disrupted crosstalk between IGF-1 signaling and the integrin mechanotransduction pathways is discussed as one of the potential mechanisms for this IGF-1 resistance. Next, emerging paradigms on bone-muscle crosstalk are examined, focusing on the potential role of IGF-1 signaling in modulating such interactions. Finally, we present a future outlook on IGF research.
    Frontiers in Endocrinology 02/2013; 4:6. DOI:10.3389/fendo.2013.00006
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