A5062845949- Parathyroid Disorders and Treatments
- Bone health and treatments
- Genetic Syndromes and Imprinting
- Bone Metabolism and Diseases
- Fibroblast Growth Factor Research
- Hedgehog Signaling Pathway Studies
- Bone health and osteoporosis research
- Vitamin D Research Studies
- Magnesium in Health and Disease
- Genetic and Kidney Cyst Diseases
- dental development and anomalies
- Metabolism, Diabetes, and Cancer
- Digestive system and related health
- Bone and Dental Protein Studies
- Cleft Lip and Palate Research
- Reproductive System and Pregnancy
- Biomedical Research and Pathophysiology
- TGF-β signaling in diseases
- Epigenetics and DNA Methylation
- NF-κB Signaling Pathways
- Growth Hormone and Insulin-like Growth Factors
- Heterotopic Ossification and Related Conditions
- Osteoarthritis Treatment and Mechanisms
- Renal and related cancers
- Immune Cell Function and Interaction
Harvard University
2014-2025
Radius Health (United States)
2018-2025
Harvard University Press
1998-2025
Rigshospitalet
2024
University of Glasgow
2024
University of Copenhagen
2024
University of Sheffield
2024
Dalhousie University
2024
University of Edinburgh
2024
MRC Centre for Reproductive Health
2024
Proper regulation of chondrocyte differentiation is necessary for the morphogenesis skeletal elements, yet little known about molecular this process. A chicken homolog Indian hedgehog (Ihh), a member conserved Hedgehog family secreted proteins that expressed during bone formation, has now been isolated. Ihh biological properties similar to those Sonic (Shh), including ability regulate targets Patched (Ptc) and Gli. in prehypertrophic chondrocytes cartilage where it regulates rate...
The PTH/PTHrP receptor binds to two ligands with distinct functions: the calcium-regulating hormone, parathyroid hormone (PTH), and paracrine factor, PTH-related protein (PTHrP). Each ligand, in turn, is likely activate more than one receptor. functions of were investigated by deletion murine gene homologous recombination. Most (−/−) mutant mice died mid-gestation, a phenotype not observed PTHrP mice, perhaps because effects maternal PTHrP. Mice that survived exhibited accelerated...
Klotho has profound effects on phosphate metabolism, but the mechanisms of how affects homeostasis is unknown. We detected in proximal tubule cell, brush border, and urinary lumen, where resides. Increasing kidney urine chronically by transgenic overexpression or acutely intravenous infusion caused hypophosphatemia, phosphaturia from decreased reabsorption, activity protein principal renal transporter NaPi-2a. The phosphaturic effect was present FGF23-null mice, indicating a direct action...
Unique among fibroblast growth factors (FGFs), FGF19, -21, and -23 act in an endocrine fashion to regulate energy, bile acid, glucose, lipid, phosphate, vitamin D homeostasis. These FGFs require the presence of Klotho/betaKlotho their target tissues. Here, we present crystal structures FGF19 alone FGF23 complex with sucrose octasulfate, a disaccharide chemically related heparin. The conformation heparin-binding region between beta strands 10 12 diverges completely from common adopted by...
Fibroblast growth factor 23 null mice (Fgf-23-/-) have a short lifespan and show numerous biochemical morphological features consistent with premature aging-like phenotypes, including kyphosis, severe muscle wasting, hypogonadism, osteopenia, emphysema, uncoordinated movement, T cell dysregulation, atrophy of the intestinal villi, skin, thymus, spleen. Furthermore, increased vitamin D activities in homozygous mutants are associated atherosclerosis widespread soft tissue calcifications;...
Klotho was discovered as an antiaging gene, and α-Klotho (Klotho) is expressed in multiple tissues with a broad set of biologic functions. Membrane-bound binds fibroblast growth factor 23 (FGF23), but soluble form also produced by alternative splicing or cleavage the extracellular domain membrane-bound protein. The relative organ-specific contributions to levels effects circulating remain unknown. We explored these issues generating novel mouse strain deleted throughout nephron...
Mice in which the genes encoding parathyroid hormone (PTH)-related peptide (PTHrP) or PTH/PTHrP receptor have been ablated by homologous recombination show skeletal dysplasia due to accelerated endochondral bone formation, and die at birth utero , respectively. Skeletal abnormalities decelerated chondrocyte maturation are observed transgenic mice where PTHrP expression is targeted growth plate, patients with Jansen metaphyseal chondrodysplasia, a rare genetic disorder caused constitutively...
To determine the role of PTHrP in fetal calcium metabolism, blood was measured mice homozygous (HOM) for deletion gene. On day 18.5 gestation, ionized and maternal–fetal gradient were significantly reduced HOM PTHrP-ablated fetuses compared with that their littermates. assess placental contribution to effect PTHrP, 45 Ca 51 Cr-EDTA (as a diffusional marker) administered by intracardiac injection pregnant, heterozygous dams on 17.5 gestation. Five minutes after injection, whole accumulation...
Parathyroid hormone-related peptide (PTHrP) is a mediator of cellular growth and differentiation as well cause malignancy-induced hypercalcemia. Most the actions PTHrP have been attributed to its interaction with specific cell surface receptor that binds N-terminal domain protein. Here we present evidence promotes some effects by translocating nucleolus. Localization transiently expressed nucleolus was dependent on presence highly basic region at carboxyl terminus molecule bears homology...
In developing murine growth plates, chondrocytes near the articular surface (periarticular chondrocytes) proliferate, differentiate into flat column-forming proliferating cells (columnar chondrocytes), stop dividing and finally hypertrophic cells. Indian hedgehog (Ihh), which is predominantly expressed in prehypertrophic cells, stimulates expression of parathyroid hormone (PTH)-related peptide (PTHrP) negatively regulates terminal chondrocyte differentiation through PTH/PTHrP receptor (PPR)....
ABSTRACT Parathyroid hormone-related protein (PTHrP) was originally discovered as a tumor product that causes humoral hypercalcemia of malignancy. PTHrP is now known to be widely expressed in normal tissues and growing evidence suggests it an important developmental regulatory molecule. We had previously reported overexpression the mammary glands transgenic mice impaired branching morphogenesis during sexual maturity early pregnancy. demonstrate plays critical role epithelial-mesenchymal...
To test the hypothesis that PTH-related peptide (PTHrP) is a paracrine regulator of endochondral bone development, we localized PTHrP and its cognate receptor during normal skeletal development at both messenger RNA (mRNA) protein levels compared growth plate phenotypes PTHrP-deficient [(PTHrP(-/-)] mice to those littermates [PTHrP(+/+]. mRNA was expressed adjacent uncavitated joints, in perichondrium long bones lower level proliferating chondrocytes. In contrast, most evident interface...
During vertebrate limb development, growth plate chondrocytes undergo temporally and spatially coordinated differentiation that is necessary for proper morphogenesis. Parathyroid hormone-related peptide (PTHrP), its receptor, the PTH/PTHrP Indian hedgehog are implicated in regulation of chondrocyte differentiation, but specific cellular targets these molecules interactions involved have not been defined. Here we generated chimeric mice containing both wild-type receptor (−/−) cells, analyzed...
Indian hedgehog (Ihh) is essential for chondrocyte and osteoblast proliferation/differentiation during prenatal endochondral bone formation. The early lethality of various Ihh-ablated mutant mice, however, prevented further analysis its role in postnatal growth development. In this study, we describe the generation characterization a mouse model which Ihh gene was successfully ablated from chondrocytes temporal/spatial-specific manner; deletion resulted loss columnar structure, premature...
A major breakthrough in systemic phosphate homeostasis regulation was achieved by the demonstration of strikingly similar physical, morphological, and biochemical phenotypes fibroblast growth factor 23 (Fgf23) klotho ablated mice, which led to identification as an Fgf23 signaling cofactor. Here, we generated double-knockout (Fgf23(-/-)/klotho(-/-)) mice test hypothesis whether has a klotho-independent function. Fgf23(-/-)/klotho(-/-) are viable have high serum levels, Fgf23(-/-) klotho(-/-)...
Parathyroid hormone (PTH) and parathyroid hormone–related peptide (PTHrP) bind to activate the same PTH/PTHrP receptor. Deletion of either PTHrP gene or receptor leads acceleration differentiation growth plate chondrocytes. To explore further functional relationships receptor, bones knockout mice were analyzed early in development, phenotypes double-knockout characterized.
Fibroblast growth factor-23 (FGF23) is a bone-derived endocrine regulator of phosphate homeostasis which inhibits renal tubular reabsorption. Binding circulating FGF23 to FGF receptors in the cell membrane requires concurrent presence co-receptor αKlotho. It still controversial whether αKlotho expressed kidney proximal tubule, principal site Hence, it has remained an enigma as how downregulates Here, we show that cells do express together with cognate receptors, and directly expression...