The calcium-sensing receptor is required for normal calcium homeostasis independent of parathyroid hormone

Kos, Claudine H.; Karaplis, Andrew C.; Ji, Peng; Hediger, Matthias A.; Goltzman, David; Mohammad, Khalid S.; Guise, Theresa A.; Pollak, Martin R.

doi:10.1172/jci17416

Cited by 177 publications

(47 citation statements)

References 47 publications

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“…Following this, the tumor-bearing hind limb bones were fixed in 10% neutral-buffered formalin, decalcified in 10% EDTA for 2 weeks, and embedded in paraffin for hematoxylin and eosin (H&E), tartrate-resistant acid phosphatase (TRAP) (Kos et al, 2003), or immunohistochemical staining. Histomorphometric analysis was performed on H&E stained bone metastasis samples using the Zeiss Axiovert 200 microscope and the AxioVision software version 4.6.3 SP1.…”

Section: Star Methodsmentioning

confidence: 99%

Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy

et al. 2017

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SUMMARY Bone metastasis is a major health threat to breast cancer patients. Tumor-derived Jagged1 represents a central node in mediating tumor-stromal interactions that promote osteolytic bone metastasis. Here, we report the development of a highly effective fully human monoclonal antibody against Jagged1 (clone 15D11). In addition to its inhibitory effect on bone metastasis of Jagged1-expressing tumor cells, 15D11 dramatically sensitizes bone metastasis to chemotherapy, which induces Jagged1 expression in osteoblasts to provide a survival niche for cancer cells. We further confirm the bone metastasis-promoting function of osteoblast-derived Jagged1 using osteoblast-specific Jagged1 transgenic mouse model. These findings establish 15D11 as a potential therapeutic agent for the prevention or treatment of bone metastasis.

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Section: Star Methodsmentioning

confidence: 99%

Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy

et al. 2017

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“…This was due to the lack of apparent skeletal defects in global CaSR −/− mice [25] that were rescued from severe hyperparathyroidism and hypercalcemia by concurrent deletion of the Gcm2 gene which specifies parathyroid development, or of the PreProPTH gene [26, 27]. It was later found that CaSR −/− mice produced a truncated CaSR with a deletion of 77 amino acids (encoded by the exon 5) in the extracellular domain.…”

Section: Casr In the Developing Skeletal Tissuementioning

confidence: 99%

The extracellular calcium-sensing receptor, CaSR, in fetal development

Riccardi

Brennan

Chang

2013

Best Practice & Research Clinical Endocrinology & Metab

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In fetal mammals, serum levels of both total and ionized calcium significantly exceed those in the adult. This relative fetal hypercalcaemia is crucial for skeletal development and is maintained irrespectively of maternal serum calcium levels. Elegant studies by Kovacs and Kronenberg have previously addressed the role of the CaSR in creating and maintaining this relative fetal hypercalcaemia, through the regulation of parathyroid hormone-related peptide secretion. More recently we have shown that the CaSR is widely distributed throughout the developing fetus, where the receptor plays major, unexpected roles in ensuring growth and maturation of several organs. In this article, we present evidence for a role of the CaSR in the control of skeletal development, and how fetal hypercalcaemia, acting through the CaSR, regulates lung development.

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“…Analyses of their bones reveled severe rickets with delayed formation of secondary ossification center, expanded and disorganized growth plate, and impaired bone formation [36, 128]. Interestingly, the growth and skeletal defects and early death of the Exon5 CaSR −/− mice could be rescued by preventing the development of HPT after breeding the mice with PTH−/− mice lacking PTH gene or Gcm2−/− mice lacking the development of PTG [129, 130]. The reversal of skeletal defects in the Exon5 CaSR −/−;PTH−/−and Exon5 CaSR −/−;Gcm2−/− double KO mice led to the conclusion that the CaSR is not essential for skeletal development [129, 130] and prompted searches for other Ca 2+ -sensing mechanism(s) [131, 132].…”

Section: Casr In Chondrocyte Differentiation and Cartilage Developmentioning

confidence: 99%

“…Interestingly, the growth and skeletal defects and early death of the Exon5 CaSR −/− mice could be rescued by preventing the development of HPT after breeding the mice with PTH−/− mice lacking PTH gene or Gcm2−/− mice lacking the development of PTG [129, 130]. The reversal of skeletal defects in the Exon5 CaSR −/−;PTH−/−and Exon5 CaSR −/−;Gcm2−/− double KO mice led to the conclusion that the CaSR is not essential for skeletal development [129, 130] and prompted searches for other Ca 2+ -sensing mechanism(s) [131, 132]. However, it was not realized at the time that the exon 5 gene-targeting strategy allowed an in-frame gene-splicing event to exclude the exon 5 along with the inserted neomycin cassette from the full-length transcript, producing a truncated CaSR lacking 77 amino acids in its ECD.…”

Section: Casr In Chondrocyte Differentiation and Cartilage Developmentioning

confidence: 99%

“…This was due to the ability of concurrent Pth or Gcm2 gene KO to rescue the skeletal defects in the global Exon5 CaSR−/− mice [184]. It was concluded at the time that the development of HPT due to defective CaSRs in PTCs was the main cause for skeletal defects observed in the Exon5 CaSR−/− mice [129, 130]. Again, follow-up studies revealed the expression of the truncated exon 5-less CaSR in the cartilage and bone of the Exon5 CaSR−/− mice.…”

Section: Actions Of Ca2+ and Casr In Bonementioning

confidence: 99%

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Interplay between CaSR and PTH1R signaling in skeletal development and osteoanabolism

Maria

Cheng

et al. 2016

Seminars in Cell & Developmental Biology

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Parathyroid hormone (PTH)-related peptide (PTHrP) controls the pace of pre- and post-natal growth plate development by activating the PTH1R in chondrocytes, while PTH maintains mineral and skeletal homeostasis by modulating calciotropic activities in kidneys, gut, and bone. The extracellular calcium-sensing receptor (CaSR) is a member of family C G protein-coupled receptor, which regulates mineral and skeletal homeostasis by controlling PTH secretion in parathyroid glands and Ca2+ excretion in kidneys. Recent studies showed the expression of CaSR in chondrocytes, osteoblasts, and osteoclasts and confirmed its non-redundant roles in modulating the recruitment, proliferation, survival, and differentiation of the cells. This review emphasizes the actions of CaSR and PTH1R signaling responses in cartilage and bone and discusses how these two signaling cascades interact to control growth plate development and maintain skeletal metabolism in physiological and pathological conditions. Lastly, novel therapeutic regimens that exploit interrelationship between the CaSR and PTH1R are proposed to produce more robust osteoanabolism.

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The calcium-sensing receptor is required for normal calcium homeostasis independent of parathyroid hormone

Cited by 177 publications

References 47 publications

Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy

Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy

The extracellular calcium-sensing receptor, CaSR, in fetal development

Interplay between CaSR and PTH1R signaling in skeletal development and osteoanabolism

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