The epithelial Ca
            <sup>2+</sup>
            channel TRPV5 is essential for proper osteoclastic bone resorption

Eerden, Bram C. J. van der; Hoenderop, Joost G. J.; Vries, Teun J. de; Schoenmaker, Ton; Buurman, C. J.; Uitterlinden, André G.; Pols, Huibert A. P.; Bindels, René J. M.; Leeuwen, Johannes P.T.M. van

doi:10.1073/pnas.0505789102

Cited by 166 publications

(180 citation statements)

References 28 publications

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“…The effects of TRPV5 channels on osteoclastic bone resorption are controversial. Van der et al22 found that bone resorption was nearly absent in osteoclast cultures from TRPV5 knock‐out mice, supporting the TRPV5‐promoted bone resorption observed in vivo. However, Nijenhuis et al23 found that TRPV5 knock‐out mice developed severe hypercalciuria and reduced bone thickness, implicated that TRPV5 may has an inhibitory effect on the process of bone resorption.…”

Section: Discussionmentioning

confidence: 84%

Regulation of TRPV5 transcription and expression by E2/ERα signalling contributes to inhibition of osteoclastogenesis

Song

Lin

et al. 2018

J Cellular Molecular Medi

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The increasing of osteoclasts formation and activity because of oestrogen (E2) deficiency is very important in the aetiology of postmenopausal osteoporosis. Our previous studies showed that E2 inhibited osteoclastic bone resorption by increasing the expression of Transient Receptor Potential Vanilloid 5 (TRPV5) channel. However, the exact mechanism by which E2 increases TRPV5 expression is not fully elucidated. In this study, Western blot, quantitative real‐time PCR, tartrate‐resistant acid phosphatase staining, F‐actin ring staining, chromatin immunoprecipitation and luciferase assay were applied to explore the mechanisms that E2‐induced TRPV5 expression contributes to the inhibition of osteoclastogenesis. The results showed that silencing or overexpressing of TRPV5 significantly affected osteoclasts differentiation and activity. Silencing of TRPV5 obviously alleviated E2‐inhibited osteoclastogenesis, resulting in increasing of bone resorption. E2 stimulated mature osteoclasts apoptosis by increasing TRPV5 expression. Further studies showed that E2 increased TRPV5 expression through the interaction of the oestrogen receptor α (ERα) with NF‐κB, which could directly bind to the fragment of −286 nt ~ −277 nt in the promoter region of trpv5. Taken together, we conclude that TRPV5 plays a dominant effect in E2‐mediated osteoclasts formation, bone resorption activity and osteoclasts apoptosis. Furthermore, NF‐κB plays an important role in the transcriptional activation of E2‐ERα stimulated TRPV5 expression.

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Section: Discussionmentioning

confidence: 84%

Regulation of TRPV5 transcription and expression by E2/ERα signalling contributes to inhibition of osteoclastogenesis

Song

Lin

et al. 2018

J Cellular Molecular Medi

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“…Furthermore, the function of spontaneously opening Ca 2C channels, which are likely to induce Ca 2C entry, is also unknown. TRPV4 channel activity has been implicated in the maintenance of intracellular Ca 2C needed for nuclear factor of activated T-cells (NFAT) activation for osteoclast differentiation (Masuyama et al 2008), and the RANKL-induced Ca 2C increase may also, in part, have extracellular origins, possibly through activation of TRPV5 channels (Bennett et al 2001, van der Eerden et al 2005, Chamoux et al 2010. It is tempting therefore, to speculate that this constitutively active current is also involved in the maintenance of NFAT expression/activity in osteoclasts.…”

Section: Discussionmentioning

confidence: 99%

Urocortin is a novel regulator of osteoclast differentiation and function through inhibition of a canonical transient receptor potential 1-like cation channel

Combs

Fuller²,

Kumar³

et al. 2011

Journal of Endocrinology

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This study investigated the role of urocortin (UCN), a member of the corticotrophin-releasing factor (CRF) family of peptides, in osteoclast maturation and function. We found that 10 K7 M UCN significantly (P!0 . 05) suppressed osteoclast differentiation from bone marrow precursor cells in culture and reduced the expression of several osteoclastic markers. Furthermore, UCN potently suppressed osteoclast bone resorption, by significantly inhibiting both the plan area of bone resorbed by osteoclasts and actin ring formation within osteoclasts at 10 K9 M (P!0 . 05), with complete inhibition at 10 K7 M (P!0 . 001). UCN also inhibited osteoclast motility (10 K7 M) but had no effect on osteoclast survival. Osteoclasts expressed mRNA encoding both UCN and the CRF receptor 2b subtype. Pre-osteoclasts however, expressed CRF receptor 2b alone. Unstimulated osteoclasts contained constitutively active cation channel currents with a unitary conductance of 3-4 pS, which were inhibited by over 70% with UCN (10 K7 M). Compounds that regulate calcium signalling and energy status of the cell, both crucial for osteoclast activity were investigated. The non-selective cation channel blockers, lanthanum (La 3C ) and gadolinium (Gd 3C ), inhibited actin ring formation in osteoclasts, whereas modulators of voltage-dependent Ca 2C channels and K ATP channels had no effect. These findings show for the first time that UCN is a novel anti-resorptive molecule that acts through a direct effect on osteoclasts and their precursor cells.

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“…(5) Interestingly, TRPV5 ablation was recently shown to result in increased numbers and size of osteoclasts, whereas osteoclast bone resorptive capacity in tibial bone marrow cultures from TRPV5 −/− mice was severely decreased. (6) These data suggested that TRPV5 is involved in osteoclast-mediated bone resorption. However, the impaired osteoclast activity seems at variance with the observed bone phenotype in TRPV5 −/− mice.…”

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confidence: 93%

“…(14) Previously, we showed that, in bone, TRPV5 localizes exclusively to the ruffled border of osteoclasts. (6) Furthermore, calbindin-D 9K , calbindin-D 28K , NCX1, and PMCA1b were shown to be present in these bone cells. (6) Together with the near absence of resorption pit formation by TRPV5 −/− osteoclasts, these data suggested that the transcellular Ca 2+ transport machinery, and TRPV5 in particular, is essential for proper osteoclastic bone resorption.…”

mentioning

confidence: 99%

“…(6) Furthermore, calbindin-D 9K , calbindin-D 28K , NCX1, and PMCA1b were shown to be present in these bone cells. (6) Together with the near absence of resorption pit formation by TRPV5 −/− osteoclasts, these data suggested that the transcellular Ca 2+ transport machinery, and TRPV5 in particular, is essential for proper osteoclastic bone resorption. (6) The balance of bone formation and resorption can be clinically influenced by the administration of bisphosphonates, which are used in the treatment of malignancyrelated hypercalcemia and osteolytic bone disease, primary and secondary hyperparathyroidism, Paget's disease of bone, and osteoporosis.…”

mentioning

confidence: 99%

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Bone Resorption Inhibitor Alendronate Normalizes the Reduced Bone Thickness of TRPV5−/− Mice

Nijenhuis

Eerden

Hoenderop

et al. 2008

Journal of Bone and Mineral Research

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TRPV5 is a Ca 2+ -selective channel involved in transcellular Ca 2+ absorption expressed in kidney and in the ruffled border of osteoclasts. Studies in hypercalciuric TRPV5 knockout (TRPV5 −/− ) mice, which display significantly increased vitamin D levels, showed that TRPV5 ablation increases number and size of osteoclasts but impairs osteoclast-mediated bone resorption. The latter is not in line with the observed decreased bone thickness in TRPV5 −/− mice. Bisphosphonates also inhibit osteoclast-mediated bone resorption. The aim of this study was to evaluate the effect of alendronate on the expression of the Ca 2+ transporters in bone, kidney, and duodenum and, importantly, the bone phenotype in TRPV5 −/− mice. Wildtype (TRPV5 +/+ ) and TRPV5−/− mice were treated during 10 wk with 2 mg/kg alendronate or vehicle weekly and housed in metabolic cages at the end of treatment. Urine and blood samples were taken for biochemical analysis, and duodenum, kidney, and femur were sampled. Expression of Ca 2+ transporters and osteoclast ruffled border transporters in bone and cultured osteoclasts was determined by QPCR analysis. Femurs were scanned using CT, and resorption pit assays were performed in bone marrow cultures isolated from TRPV5 +/+ and TRPV5 −/− mice. Alendronate treatment enhanced bone thickness in TRPV5 +/+ mice but also normalized the disturbed bone morphometry parameters in TRPV5 −/− mice. Bone TRPV5 expression was specifically enhanced by alendronate, whereas the expression of Ca 2+ transporters in kidney and intestine was not altered. The expression of the osteoclast ruffled border membrane proteins chloride channel 7 (CLC-7) and the vacuolar H + -ATPase did not differ between both genotypes, but alendronate significantly enhanced the expression and PTH levels in TRPV5 −/− mice. The expression of TRPV5, CLC-7, and H + -ATPase in osteoclast cultures was not affected by alendronate. The number of resorption pits was reduced in TRPV5 −/− bone marrow cultures, but the response to vitamin D was similar to that in TRPV5 +/+ cultures. The alendronate-induced upregulation of TRPV5 in bone together with the decreased resorptive capacity of TRPV5 −/− osteoclasts in vitro suggests that TRPV5 has an important role in osteoclast function. However, our data indicate that significant bone resorption still occurs in TRPV5 −/− mice, because alendronate treatment normalized bone thickness in these mice. Thus, TRPV5 −/− mice are able to rescue the resulting defect in osteoclast-mediated bone resorption, possibly mediated by the long-term hypervitaminosis D or other (non)hormonal compensatory mechanisms.

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

Cited by 166 publications

References 28 publications

Regulation of TRPV5 transcription and expression by E2/ERα signalling contributes to inhibition of osteoclastogenesis

Regulation of TRPV5 transcription and expression by E2/ERα signalling contributes to inhibition of osteoclastogenesis

Urocortin is a novel regulator of osteoclast differentiation and function through inhibition of a canonical transient receptor potential 1-like cation channel

Bone Resorption Inhibitor Alendronate Normalizes the Reduced Bone Thickness of TRPV5−/− Mice

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

Cited by 166 publications

References 28 publications

Regulation of TRPV5 transcription and expression by E2/ERα signalling contributes to inhibition of osteoclastogenesis

Regulation of TRPV5 transcription and expression by E2/ERα signalling contributes to inhibition of osteoclastogenesis

Urocortin is a novel regulator of osteoclast differentiation and function through inhibition of a canonical transient receptor potential 1-like cation channel

Bone Resorption Inhibitor Alendronate Normalizes the Reduced Bone Thickness of TRPV5−/− Mice

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