Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5

Hoenderop, Joost G. J.; Leeuwen, Johannes P.T.M. van; Eerden, Bram C. J. van der; Kersten, Ferry F.J.; derKemp, Annemiete W.C.M. van; Mérillat, Anne-Marie; Waarsing, J.H.; Rossier, Bernard C.; Vallon, Volker; Hummler, Edith; Bindels, René J. M.

doi:10.1172/jci19826

Cited by 225 publications

(248 citation statements)

References 28 publications

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“…Importantly, serum 1,25(OH) 2 D 3 levels were elevated, causing an compensatory increase in intestinal TRPV6 and calbindin-D 9K mRNA expression as well as Ca 2+ absorption in TRPV5 −/− mice, explaining the remaining normal serum Ca 2+ levels. Furthermore, the TRPV5 −/− mice exhibited significant disturbances in bone structure, including reduced trabecular and cortical bone thickness compared to TRPV5 +/+ mice (Hoenderop et al 2003a). Together, ablation of the TRPV5 gene seriously disturbed renal Ca 2+ handling, resulting in compensatory intestinal hyperabsorption and bone abnormalities.…”

Section: Trpv5 Knockout Micementioning

confidence: 99%

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The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease

Abel

Hoenderop

Bindels

2005

Naunyn-Schmiedeberg's Arch Pharmacol

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The epithelial Ca 2+ channels TRPV5 and TRPV6 represent a new family of Ca 2+ channels that belongs to the superfamily of transient receptor potential channels. TRPV5 and TRPV6 constitute the apical Ca 2+ entry mechanism in active Ca 2+ transport in kidney and intestine. The central role of TRPV5 and TRPV6 in active Ca 2+ (re)absorption makes it a prime target for regulation to maintain Ca 2+ balance. This review covers the hormonal regulation, interaction with accessory proteins and (patho)physiological implications of these epithelial Ca 2+ channels.

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Section: Trpv5 Knockout Micementioning

confidence: 99%

“…In order to investigate the physiological function of TRPV5 in maintaining Ca 2+ balance, TRPV5 knockout mice were generated (Hoenderop et al 2003a). Mice lacking TRPV5 (TRPV5 −/− ) displayed a significant calciuresis compared to their wild-type littermates (TRPV5 +/+ ) while remaining normocalcemic.…”

Section: Trpv5 Knockout Micementioning

confidence: 99%

The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease

Abel

Hoenderop

Bindels

2005

Naunyn-Schmiedeberg's Arch Pharmacol

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“…In a recent study, we generated mice lacking TRPV5 (TRPV5 Ϫ/Ϫ ), which displayed severe renal Ca 2ϩ wasting and compensatory intestinal hyperabsorption of Ca 2ϩ . Moreover, the knockout mice exhibited significant disturbances in bone structure, including reduced femoral cortical and trabecular bone thickness (7).…”

mentioning

confidence: 99%

The epithelial Ca ²⁺ channel TRPV5 is essential for proper osteoclastic bone resorption

Eerden

Hoenderop

Vries

et al. 2005

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

166

169

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Bone remodeling involves the interplay of bone resorption and formation and is accurately controlled to maintain bone mass. Both processes require transcellular Ca 2؉ transport, but the molecular mechanisms engaged remain largely elusive. The epithelial Ca 2؉ channel TRPV5 is one of the most Ca 2؉ -selective transient receptor potential (TRP) channels. In this study, the functional role of TRPV5 in bone was investigated. TRPV5 mRNA was expressed in human and murine bone samples and in osteoclasts along with other genes involved in transcellular Ca 2؉ transport, including calbindin-D9K and calbindin-D28K, Na ؉ ͞Ca 2؉ exchanger 1, and plasma membrane Ca 2؉ -ATPase 1b. TRPV5 expression in murine osteoclasts was confirmed by immunostaining and showed predominant localization to the ruffled border membrane. However, TRPV5 was absent in osteoblasts. Analyses of femoral bone sections from TRPV5 knockout (TRPV5 ؊͞؊ ) mice revealed increased osteoclast numbers and osteoclast area, whereas the urinary bone resorption marker deoxypyridinoline was reduced compared with WT (TRPV5 ؉͞؉ ) mice. In an in vitro bone marrow culture system, the amount of osteoclasts and number of nuclei per osteoclast were significantly elevated in TRPV5 ؊/؊ compared with TRPV5 ؉/؉ mice. However, using a functional resorption pit assay, we found that bone resorption was nearly absent in osteoclast cultures from TRPV5 ؊/؊ mice, supporting the impaired resorption observed in vivo. In conclusion, TRPV5 deficiency leads to an increase in osteoclast size and number, in which Ca 2؉ resorption is nonfunctional. This report identifies TRPV5 as an epithelial Ca 2؉ channel that is essential for osteoclastic bone resorption and demonstrates the significance of transcellular Ca 2؉ transport in osteoclastic function.tartrate-resistant acid phosphatase ͉ 1,25(OH)2D3 ͉ osteoblast ͉ Coomassie blue ͉ laser scanning confocal microscopy M aintenance of body Ca 2ϩ is of crucial importance for many physiological functions, including neuronal excitability, muscle contraction, and bone formation. Bone is the major Ca 2ϩ storage of the body and regulates in concerted action with kidney and intestine the whole-body Ca 2ϩ balance. Transcellular Ca 2ϩ transport is an important process in maintaining Ca 2ϩ balance by these tissues (1, 2). In bone, it is crucial for bone formation͞ mineralization to achieve adequate bone quality and strength, but also for osteoclastic bone resorption, which contributes to Ca 2ϩ balance in the blood. However, the proteins involved in transcellular Ca 2ϩ transport in bone cells are largely elusive. Recently, TRPV5 and TRPV6, members of the superfamily of transient receptor potential (TRP) cation channels, have been identified as the gatekeepers of transepithelial Ca 2ϩ transport in kidney and intestine, respectively (3-5). These highly selective epithelial Ca 2ϩ channels are part of a three-step process, facilitating transcellular Ca 2ϩ transport (3, 4, 6). After entry of Ca 2ϩ into the cell through TRPV5 and TRPV6, Ca 2ϩ bound to calbindin-D 28...

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“…The role of TRPV6 in this segment remains to be identified. Mice with targeted ablation of TRPV5 have been generated (91) and exhibit polyuria and hypercalciuria, providing support for an essential role of TRPV5 in renal Ca 2ϩ reabsorption. Consistent with the phenotype of renal Ca 2ϩ wasting, TRPV5 knockout animals exhibit compensatory intestinal hyperabsorption of Ca 2ϩ and reduced bone thickness.…”

Section: Role Of Trp In Divalent Ion Homeostasismentioning

confidence: 98%

The Transient Receptor Potential Superfamily of Ion Channels

Huang

2004

Journal of the American Society of Nephrology

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Abstract. The transient receptor potential (TRP) superfamily of proteins is cation-selective ion channels with six predicted transmembrane segments and intracellularly localized amino and carboxyl termini. Members of the TRP superfamily are identified on the basis of amino acid sequence and structural similarity and are classified into TRPC, TRPV, TRPM, TRPP, TRPN, and TRPML subfamilies. TRP channels are widespread and have diverse functions, ranging from thermal, tactile, taste, osmolar, and fluid flow sensing to transepithelial Ca 2ϩ and Mg 2ϩ transport. Mutations of TRP proteins produce many renal diseases, including Mg 2ϩ wasting, hypocalcemia, and polycystic kidney diseases. This review focuses on recent advances in the understanding of their functions.The first transient receptor potential (TRP) protein was discovered in studies that examined Drosophila phototransduction (1). The photoreceptor cells of Drosophila exhibit sustained receptor potentials in response to continuous light exposure. The ionic basis for the sustained receptor potentials is influx of Ca 2ϩ from the extracellular space. Cosens and Manning (1) reported in 1969 that one group of mutant flies exhibits TRP upon continuous light exposure and named it trp, for transient receptor potential. The trp gene was cloned in 1989 (2) and subsequently shown to encode a Ca 2ϩ -permeable cation channel (3). Since then, many channels that bear sequence and structural similarities to the Drosophila TRP have been cloned from flies, worms, and mammals. Together, they form the TRP superfamily.Ion channels (e.g., voltage-gated K ϩ channels) are typically identified by their modes of activation and/or ion selectivity. Each family or superfamily of ion channels of similar activation and selectivity consists of multiple members of channel proteins with amino acid sequence homology. Unlike most ion channel families, the TRP superfamily of ion channels are identified on the basis of homology only. The mode of activation and selectivity for TRP channels are disparate. Some TRP channels are activated by ligands, whereas others are regulated by physical stimuli (e.g., heat) or yet-unknown mechanisms. All TRP channels are cation selective, but the selectivity ratio for Ca 2ϩ versus the monovalent cation Na ϩ (P Ca /P Na ) varies widely, ranging from Ͼ100:1, to 1 to 10:1, to Ͻ0.05:1. The lack of common identifying features has in part contributed to the confusing nomenclature of TRP channels in the literature.A recent consensus report proposed a unified nomenclature for the TRP superfamily (4). It classified TRP channels into TRPC, TRPV, and TRPM subfamilies. More recent classification has expanded TRP superfamily to include three additional, more distantly related subfamilies, TRPP, TRPML, and TRPN ( Figure 1). Structurally, all of these TRP channels have six predicted transmembrane (TM) segments and N-terminal and C-terminal cytoplasmic tails similar to topologies of voltagegated K ϩ , Na ϩ , and Ca 2ϩ channels; cyclic nucleotide-gated channels; and hyperpolarizati...

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Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5

Cited by 225 publications

References 28 publications

The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease

The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease

The epithelial Ca ²⁺ channel TRPV5 is essential for proper osteoclastic bone resorption

The Transient Receptor Potential Superfamily of Ion Channels

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Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5

Cited by 225 publications

References 28 publications

The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease

The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease

The epithelial Ca 2+ channel TRPV5 is essential for proper osteoclastic bone resorption

The Transient Receptor Potential Superfamily of Ion Channels

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The epithelial Ca ²⁺ channel TRPV5 is essential for proper osteoclastic bone resorption