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

Hanabusa, Takao; Chagin, Andrei S.; Kobayashi, Tatsuya; Mackem, Susan; Kronenberg, Henry M.

doi:10.1073/pnas.1005011108

Cited by 91 publications

(89 citation statements)

References 26 publications

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“…Col11a2-hSIK3 transgenic mice showed early closure of the growth plates. Growth plate disappearance has been reported in mice in which IHH (Maeda et al, 2007) and the PTH/PTHrP receptor (Hirai et al, 2011) were deleted postnatally. Because IHH and PTH/PTHrP regulate chondrocyte hypertrophy, SIK3 might be localized and controlled by these signaling molecules during the progression of chondrocyte hypertrophy.…”

Section: Molecular Mechanisms By Which Sik3 Exerts Its Activity In Chmentioning

confidence: 99%

SIK3 is essential for chondrocyte hypertrophy during skeletal development in mice

et al. 2012

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SUMMARYChondrocyte hypertrophy is crucial for endochondral ossification, but the mechanism underlying this process is not fully understood. We report that salt-inducible kinase 3 (SIK3) deficiency causes severe inhibition of chondrocyte hypertrophy in mice. SIK3-deficient mice showed dwarfism as they aged, whereas body size was unaffected during embryogenesis. Anatomical and histological analyses revealed marked expansion of the growth plate and articular cartilage regions in the limbs, accumulation of chondrocytes in the sternum, ribs and spine, and impaired skull bone formation in SIK3-deficient mice. The primary phenotype in the skeletal tissue of SIK3-deficient mice was in the humerus at E14.5, where chondrocyte hypertrophy was markedly delayed. Chondrocyte hypertrophy was severely blocked until E18.5, and the proliferative chondrocytes occupied the inside of the humerus. Consistent with impaired chondrocyte hypertrophy in SIK3-deficient mice, native SIK3 expression was detected in the cytoplasm of prehypertrophic and hypertrophic chondrocytes in developing bones in embryos and in the growth plates in postnatal mice. HDAC4, a crucial repressor of chondrocyte hypertrophy, remained in the nuclei in SIK3-deficient chondrocytes, but was localized in the cytoplasm in wild-type hypertrophic chondrocytes. Molecular and cellular analyses demonstrated that SIK3 was required for anchoring HDAC4 in the cytoplasm, thereby releasing MEF2C, a crucial facilitator of chondrocyte hypertrophy, from suppression by HDAC4 in nuclei. Chondrocyte-specific overexpression of SIK3 induced closure of growth plates in adulthood, and the SIK3-deficient cartilage phenotype was rescued by transgenic SIK3 expression in the humerus. These results demonstrate an essential role for SIK3 in facilitating chondrocyte hypertrophy during skeletogenesis and growth plate maintenance.

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Section: Molecular Mechanisms By Which Sik3 Exerts Its Activity In Chmentioning

confidence: 99%

SIK3 is essential for chondrocyte hypertrophy during skeletal development in mice

et al. 2012

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“…The phenotype in S1P cko-ER(T) mice is neither due to the loss of PTHrP-R expression as postnatal loss of PTHrP-R demonstrates accelerated chondrocyte differentiation (22) as opposed to the loss of differentiation seen on postnatal S1P ablation.…”

Section: Discussionmentioning

confidence: 98%

“…Our time course studies clearly demonstrate that apoptosis is not immediate and is therefore ancillary to the concomitant processes of intracellular Col IIB retention and disruption of hypertrophic differentiation. Mechanistically, this is indicative of the perturbation of developmental pathways different from that regulated by other growth plate molecules such as PTHrP-R whose postnatal ablation is characterized by apoptotic events fundamental to growth plate closure (22). Although the growth plate in S1P cko-ER(T) is rendered inactive due to loss of hypertrophy, with time it is also rendered nonexistent due to apoptotic activity.…”

Section: Cko-er(t)mentioning

confidence: 99%

Site-1 Protease Is Essential to Growth Plate Maintenance and Is a Critical Regulator of Chondrocyte Hypertrophic Differentiation in Postnatal Mice

Patra

DeLassus

Hayashi

et al. 2011

Journal of Biological Chemistry

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Site-1 protease (S1P) is a proprotein convertase with essential functions in lipid homeostasis and unfolded protein response pathways. We previously studied a mouse model of cartilage-specific knock-out of S1P in chondroprogenitor cells. These mice exhibited a defective cartilage matrix devoid of type II collagen protein (Col II) and displayed chondrodysplasia with no endochondral bone formation even though the molecular program for endochondral bone development appeared intact. To gain insights into S1P function, we generated and studied a mouse model in which S1P is ablated in postnatal chondrocytes. Postnatal ablation of S1P results in chondrodysplasia. However, unlike early embryonic ablations, the growth plates of these mice exhibit a lack of Ihh, PTHrP-R, and Col10 expression indicating a loss of chondrocyte hypertrophic differentiation and thus disruption of the molecular program required for endochondral bone development. S1P ablation results in rapid growth plate disruption due to intracellular Col II entrapment concomitant with loss of chondrocyte hypertrophy suggesting that these two processes are related. Entrapment of Col II in the chondrocytes of the prospective secondary ossification center precludes its development. Trabecular bone formation is dramatically diminished in the primary spongiosa and is eventually lost. The primary growth plate is eradicated by apoptosis but is gradually replaced by a fully functional new growth plate from progenitor stem cells capable of supporting new bone growth. Our study thus demonstrates that S1P has fundamental roles in the preservation of postnatal growth plate through chondrocyte differentiation and Col II deposition and functions to couple growth plate maturation to trabecular bone development in growing mice.Site-1 protease (S1P 3 ; also known as the membrane-bound transcription factor protease, site-1) is a proprotein convertase that plays a vital role in maintaining lipid homeostasis and unfolded protein response through regulated intramembrane proteolysis pathways. During lipid homeostasis, S1P is involved in the proteolytic maturation of the latent endoplasmic reticulum membrane-bound sterol regulatory element-binding protein transcription factors that direct the synthesis of proteins involved in cholesterol and fatty acid synthesis and uptake (1, 2). During unfolded protein response, S1P is involved in the maturation of the endoplasmic reticulum membrane-bound transcription factors ATF6 (3), old astrocyte specifically induced substance (4), and cAMP-responsive element-binding protein H (5).Several recent studies have also implicated a role for S1P in skeletal development, although the exact molecular nature of this requirement is not known. Mammalian skeletal development takes place largely through the process of endochondral ossification in which mesenchymal cell condensates differentiate to form chondrocytes. Chondrocytes secrete the type II collagen (Col II)-rich cartilaginous anlagen to form a template for the development of the skeletal structura...

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“…This new syndrome, named pseudopseudohypoparathyroidism (PPHP; OMIM #612463) may be present either in kindreds with PHP or as an isolated defect. It is possible that the 'bone phenotype' observed in AHO is largely mediated by the resistance to PTHrP at the growth plate during foetal and postnatal growth (31).…”

Section: Figurementioning

confidence: 99%

From pseudohypoparathyroidism to inactivating PTH/PTHrP signalling disorder (iPPSD), a novel classification proposed by the EuroPHP network

Thiele

Mantovani

Barlier

et al. 2016

European Journal of Endocrinology

123

113

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Objective: Disorders caused by impairments in the parathyroid hormone (PTH) signalling pathway are historically classified under the term pseudohypoparathyroidism (PHP), which encompasses rare, related and highly heterogeneous diseases with demonstrated (epi)genetic causes. The actual classification is based on the presence or absence of specific clinical and biochemical signs together with an in vivo response to exogenous PTH and the results of an in vitro assay to measure Gsa protein activity. However, this classification disregards other related diseases such as acrodysostosis (ACRDYS) or progressive osseous heteroplasia (POH), as well as recent findings of clinical and genetic/epigenetic background of the different subtypes. Therefore, the EuroPHP network decided to develop a new classification that encompasses all disorders with impairments in PTH and/or PTHrP cAMP-mediated pathway. Design and methods: Extensive review of the literature was performed. Several meetings were organised to discuss about a new, more effective and accurate way to describe disorders caused by abnormalities of the PTH/PTHrP signalling pathway. Results and conclusions: After determining the major and minor criteria to be considered for the diagnosis of these disorders, we proposed to group them under the term 'inactivating PTH/PTHrP signalling disorder' (iPPSD). This terminology: (i) defines the common mechanism responsible for all diseases; (ii) does not require a confirmed genetic defect; (iii) avoids ambiguous terms like 'pseudo' and (iv) eliminates the clinical or molecular overlap

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

Cited by 91 publications

References 26 publications

SIK3 is essential for chondrocyte hypertrophy during skeletal development in mice

SIK3 is essential for chondrocyte hypertrophy during skeletal development in mice

Site-1 Protease Is Essential to Growth Plate Maintenance and Is a Critical Regulator of Chondrocyte Hypertrophic Differentiation in Postnatal Mice

From pseudohypoparathyroidism to inactivating PTH/PTHrP signalling disorder (iPPSD), a novel classification proposed by the EuroPHP network

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