Absence of functional receptors for parathyroid hormone and parathyroid hormone-related peptide in Blomstrand chondrodysplasia.

Jobert, Anne-Sixtine; Zhang, Ping; Couvineau, Alain; Bonaventure, Jacky; Roume, J.; Merrer, Martine Le; Silve, Caroline

doi:10.1172/jci2918

Cited by 304 publications

(136 citation statements)

References 34 publications

(36 reference statements)

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“…Previous studies have clearly documented the indispensable biological importance of PTHrP/PTH1R signaling in skeletal (11)(12)(13)(14)(15) and mammary gland (16,17) development. Additional endocrine and paracrine functions have been ascribed to the mid-region and C-terminal region (107 to 139) of the molecule (18,19).…”

Section: Ntranuclear Transport Of Numerous Polypeptide Ligands Has mentioning

confidence: 99%

Severe growth retardation and early lethality in mice lacking the nuclear localization sequence and C-terminus of PTH-related protein

Miao

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

113

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Parathyroid hormone (PTH) plays a central role in the regulation of serum calcium and phosphorus homeostasis, while parathyroid hormone-related protein (PTHrP) has important developmental roles. Both peptides signal through the same G protein-coupled receptor, the PTH/PTHrP or PTH type 1 receptor (PTH1R). PTHrP, normally a secreted protein, also contains a nuclear localization signal (NLS) that in vitro imparts functionality to the protein at the level of the nucleus. We investigated this functionality in vivo by introducing a premature termination codon in Pthrp in ES cells and generating mice that express PTHrP (1-84), a truncated form of the protein that is missing the NLS and the C-terminal region of the protein but can still signal through its cell surface receptor. Mice homozygous for the knock-in mutation (Pthrp KI) displayed retarded growth, early senescence, and malnutrition leading postnatally to their rapid demise. Decreased cellular proliferative capacity and increased apoptosis in multiple tissues including bone and bone marrow cells were associated with altered expression and subcellular distribution of the senescenceassociated tumor suppressor proteins p16 INK4a and p21 and the oncogenes Cyclin D, pRb, and Bmi-1. These findings provide in vivo experimental proof that substantiates the biologic relevance of the NLS and C-terminal portion of PTHrP, a polypeptide ligand that signals mainly via a cell surface G protein-coupled receptor.ageing ͉ nucleus ͉ osteoporosis ͉ PTHrP ͉ senescence

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Section: Ntranuclear Transport Of Numerous Polypeptide Ligands Has mentioning

confidence: 99%

Severe growth retardation and early lethality in mice lacking the nuclear localization sequence and C-terminus of PTH-related protein

Miao

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

113

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“…In similar fashion, people heterozygous for inactivating mutations of the gene encoding PTHrP exhibit short metacarpals, metatarsals, and phalanges, along with premature cessation of growth leading to short stature (6,7). Because PTHrP activates the PPR and then Gsα, and because the KO of Gsα in the growth plate of mice leads to accelerated chondrocyte differentiation resembling that of the PPR KO (4,20), it is plausible that the growth plate closure in AHO and human heterozygosity for the PTHrP gene result from processes like those demonstrated here. Growth plate closure is also seen when Ihh is knocked out postnatally in the growth plate (21) or when hedgehog antagonists are administered to mice (22).…”

Section: Discussionmentioning

confidence: 95%

Parathyroid hormone/parathyroid hormone-related protein receptor signaling is required for maintenance of the growth plate in postnatal life

Hanabusa

Chagin

Kobayashi

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Parathyroid hormone (PTH)-related protein (PTHrP), regulated by Indian hedgehog and acting through the PTH/PTHrP receptor (PPR), is crucial for normal cartilage development. These observations suggest a possible role of PPR signaling in the postnatal growth plate; however, the role of PPR signaling in postnatal chondrocytes is unknown. In this study, we have generated tamoxifen-inducible and cartilage-specific PPR KO mice to evaluate the physiological role of PPR signaling in postnatal chondrocytes. We found that inactivation of the PPR in chondrocytes postnatally leads to accelerated differentiation of chondrocytes, followed by disappearance of the growth plate. We also observed an increase of TUNEL-positive cells and activities of caspase-3 and caspase-9 in the growth plate, along with a decrease in phosphorylation of Bad at Ser155 in postnatal PPR KO mice. Administration of a lowphosphate diet, which prevents apoptosis of chondrocytes, prevented the disappearance of the growth plate. Taken together, these observations suggest that the major consequences of PPR activation are similar in both the fetal and postnatal growth plates. Moreover, chondrocyte apoptosis through the activation of a mitochondrial pathway may be involved in the process of premature disappearance of the growth plate by postnatal inactivation of the PPR in chondrocytes.

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“…Conversely, misexpression of PTHrP in all chondrocytes markedly delayed chondrocyte hypertrophy, resulting in a completely cartilaginous endochondral skeleton at birth (Weir et al 1996). Similarly in humans, inactivating mutations in PTHR1 cause Blomstrand chondrodysplasia, characterized by advanced skeletal maturation with shortened long bones and increased bone density (Jobert et al 1998;Karaplis et al 1998;Karperien et al 1999), whereas gain-offunction mutations in PTHR1 cause Jansen metaphyseal chondrodysplasia (Schipani et al 1995(Schipani et al , 1996, which was recapitulated in mice overexpressing such a mutant receptor (Schipani et al 1997). Mechanistically, PTHrP appears to delay chondrocyte hypertrophy, mainly by activating cAMP-dependent signaling that both increases the activity of SOX9 Guo et al 2002), and regulates the HDAC4-MEF2C complex (see below).…”

Section: Pthrpmentioning

confidence: 99%

Development of the Endochondral Skeleton

Long

Ornitz

2013

Cold Spring Harbor Perspectives in Biology

519

493

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SUMMARYMuch of the mammalian skeleton is composed of bones that originate from cartilage templates through endochondral ossification. Elucidating the mechanisms that control endochondral bone development is critical for understanding human skeletal diseases, injury response, and aging. Mouse genetic studies in the past 15 years have provided unprecedented insights about molecules regulating chondrocyte formation, chondrocyte maturation, and osteoblast differentiation, all key processes of endochondral bone development. These include the roles of the secreted proteins IHH, PTHrP, BMPs, WNTs, and FGFs, their receptors, and transcription factors such as SOX9, RUNX2, and OSX, in regulating chondrocyte and osteoblast biology. This review aims to integrate the known functions of extracellular signals and transcription factors that regulate development of the endochondral skeleton.

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Absence of functional receptors for parathyroid hormone and parathyroid hormone-related peptide in Blomstrand chondrodysplasia.

Abstract: We report the absence of functional parathyroid hormone (PTH)/PTH-related peptide (

Cited by 304 publications

References 34 publications

Severe growth retardation and early lethality in mice lacking the nuclear localization sequence and C-terminus of PTH-related protein

Severe growth retardation and early lethality in mice lacking the nuclear localization sequence and C-terminus of PTH-related protein

Parathyroid hormone/parathyroid hormone-related protein receptor signaling is required for maintenance of the growth plate in postnatal life

Development of the Endochondral Skeleton

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