{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T17:52:25Z","timestamp":1776880345038,"version":"3.51.2"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2008,11,1]],"date-time":"2008-11-01T00:00:00Z","timestamp":1225497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>TRPV5 is a Ca2+-selective channel involved in transcellular Ca2+ absorption expressed in kidney and in the ruffled border of osteoclasts. Studies in hypercalciuric TRPV5 knockout (TRPV5\u2212\/\u2212) 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\u2212\/\u2212 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 Ca2+ transporters in bone, kidney, and duodenum and, importantly, the bone phenotype in TRPV5\u2212\/\u2212 mice. Wildtype (TRPV5+\/+) and TRPV5\u2212\/\u2212 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 Ca2+ transporters and osteoclast ruffled border transporters in bone and cultured osteoclasts was determined by QPCR analysis. Femurs were scanned using \u03bcCT, and resorption pit assays were performed in bone marrow cultures isolated from TRPV5+\/+ and TRPV5\u2212\/\u2212 mice. Alendronate treatment enhanced bone thickness in TRPV5+\/+ mice but also normalized the disturbed bone morphometry parameters in TRPV5\u2212\/\u2212 mice. Bone TRPV5 expression was specifically enhanced by alendronate, whereas the expression of Ca2+ 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\u2212\/\u2212 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\u2212\/\u2212 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\u2212\/\u2212 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\u2212\/\u2212 mice, because alendronate treatment normalized bone thickness in these mice. Thus, TRPV5\u2212\/\u2212 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.<\/jats:p>","DOI":"10.1359\/jbmr.080613","type":"journal-article","created":{"date-parts":[[2008,7,2]],"date-time":"2008-07-02T20:10:38Z","timestamp":1215029438000},"page":"1815-1824","source":"Crossref","is-referenced-by-count":27,"title":["Bone Resorption Inhibitor Alendronate Normalizes the Reduced Bone Thickness of TRPV5\u2212\/\u2212 Mice"],"prefix":"10.1093","volume":"23","author":[{"given":"Tom","family":"Nijenhuis","sequence":"first","affiliation":[{"name":"Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen Medical Centre, Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bram CJ","family":"van der Eerden","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joost GJ","family":"Hoenderop","sequence":"additional","affiliation":[{"name":"Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen Medical Centre, Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harrie","family":"Weinans","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Erasmus Medical Centre, Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes PTM","family":"van Leeuwen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ren\u00e9 JM","family":"Bindels","sequence":"additional","affiliation":[{"name":"Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen Medical Centre, Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2009,12,4]]},"reference":[{"key":"2024020319474603200_bib1","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1152\/physrev.00003.2004","article-title":"Calcium absorption across epithelia","volume":"85","author":"Hoenderop","year":"2005","journal-title":"Physiol Rev"},{"key":"2024020319474603200_bib2","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/s00424-005-1430-6","article-title":"TRPV5 and TRPV6 in Ca2+ (re)absorption: Regulating Ca2+ entry at the gate","volume":"451","author":"Nijenhuis","year":"2005","journal-title":"Pflugers Arch"},{"key":"2024020319474603200_bib3","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/nature01660","article-title":"Control of osteoblast function and regulation of bone mass","volume":"423","author":"Harada","year":"2003","journal-title":"Nature"},{"key":"2024020319474603200_bib4","doi-asserted-by":"crossref","first-page":"2731","DOI":"10.1097\/01.ASN.0000094081.78893.E8","article-title":"Localization and regulation of the epithelial Ca2+ channel TRPV6 in the kidney","volume":"14","author":"Nijenhuis","year":"2003","journal-title":"J Am Soc Nephrol"},{"key":"2024020319474603200_bib5","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1172\/JCI200319826","article-title":"Renal Ca2+ wasting, hyperabsorption and reduced bone thickness in mice lacking TRPV5","volume":"112","author":"Hoenderop","year":"2003","journal-title":"J Clin Invest"},{"key":"2024020319474603200_bib6","doi-asserted-by":"crossref","first-page":"17507","DOI":"10.1073\/pnas.0505789102","article-title":"The epithelial Ca2+ channel TRPV5 is essential for proper osteoclastic bone resorption","volume":"102","author":"van der Eerden","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024020319474603200_bib7","doi-asserted-by":"crossref","first-page":"8375","DOI":"10.1074\/jbc.274.13.8375","article-title":"Molecular identification of the apical Ca2+ channel in 1, 25-dihydroxyvitamin D3-responsive epithelia","volume":"274","author":"Hoenderop","year":"1999","journal-title":"J Biol Chem"},{"key":"2024020319474603200_bib8","doi-asserted-by":"crossref","first-page":"22739","DOI":"10.1074\/jbc.274.32.22739","article-title":"Molecular cloning and characterization of a channel-like transporter mediating intestinal calcium absorption","volume":"274","author":"Peng","year":"1999","journal-title":"J Biol Chem"},{"key":"2024020319474603200_bib9","doi-asserted-by":"crossref","first-page":"1968","DOI":"10.1359\/jbmr.070801","article-title":"Phenotype of a calbindin-D9k gene knockout is compensated for by the induction of other calcium transporter genes in a mouse model","volume":"22","author":"Lee","year":"2007","journal-title":"J Bone Miner Res"},{"key":"2024020319474603200_bib10","doi-asserted-by":"crossref","first-page":"12377","DOI":"10.1073\/pnas.0605252103","article-title":"Calbindin D(9k) knockout mice are indistinguishable from wild-type mice in phenotype and serum calcium level","volume":"103","author":"Kutuzova","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024020319474603200_bib11","doi-asserted-by":"crossref","first-page":"52406","DOI":"10.1074\/jbc.M405562200","article-title":"Critical role of calbindin-D28k in calcium homeostasis revealed by mice lacking both vitamin D receptor and calbindin-D28k","volume":"279","author":"Zheng","year":"2004","journal-title":"J Biol Chem"},{"key":"2024020319474603200_bib12","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1172\/JCI24134","article-title":"Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia","volume":"115","author":"Nijenhuis","year":"2005","journal-title":"J Clin Invest"},{"key":"2024020319474603200_bib13","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1111\/j.1523-1755.2005.00587.x","article-title":"Coordinated control of renal Ca2+ transport proteins by parathyroid hormone","volume":"68","author":"van Abel","year":"2005","journal-title":"Kidney Int"},{"key":"2024020319474603200_bib14","doi-asserted-by":"crossref","first-page":"3188","DOI":"10.1681\/ASN.2005060632","article-title":"Hypervitaminosis D mediates compensatory Ca2+ hyperabsorption in TRPV5 knockout mice","volume":"16","author":"Renkema","year":"2005","journal-title":"J Am Soc Nephrol"},{"key":"2024020319474603200_bib15","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s11914-003-0008-5","article-title":"Mechanism of action of bisphosphonates","volume":"1","author":"Reszka","year":"2003","journal-title":"Curr Osteoporos Rep"},{"issue":"12 Suppl","key":"2024020319474603200_bib16","doi-asserted-by":"crossref","first-page":"2961","DOI":"10.1002\/1097-0142(20000615)88:12+<2961::AID-CNCR12>3.0.CO;2-L","article-title":"Cellular and molecular mechanisms of action of bisphosphonates","volume":"88","author":"Rogers","year":"2000","journal-title":"Cancer"},{"key":"2024020319474603200_bib17","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1681\/ASN.V1271342","article-title":"Calcitriol controls the epithelial calcium channel in kidney","volume":"12","author":"Hoenderop","year":"2001","journal-title":"J Am Soc Nephrol"},{"key":"2024020319474603200_bib18","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1046\/j.1523-1755.2003.00128.x","article-title":"Thiazide-induced hypocalciuria is accompanied by a decreased expression of Ca2+ transporting proteins in the distal tubule","volume":"64","author":"Nijenhuis","year":"2003","journal-title":"Kidney Int"},{"key":"2024020319474603200_bib19","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/77131","article-title":"Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis","volume":"25","author":"Frattini","year":"2000","journal-title":"Nat Genet"},{"key":"2024020319474603200_bib20","doi-asserted-by":"crossref","first-page":"2861","DOI":"10.1093\/hmg\/10.25.2861","article-title":"Albers-Schonberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene","volume":"10","author":"Cleiren","year":"2001","journal-title":"Hum Mol Genet"},{"key":"2024020319474603200_bib21","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S0092-8674(01)00206-9","article-title":"Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man","volume":"104","author":"Kornak","year":"2001","journal-title":"Cell"},{"key":"2024020319474603200_bib22","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1093\/hmg\/9.13.2059","article-title":"Mutations in the a3 subunit of the vacuolar H+-ATPase cause infantile malignant osteopetrosis","volume":"9","author":"Kornak","year":"2000","journal-title":"Hum Mol Genet"},{"key":"2024020319474603200_bib23","doi-asserted-by":"crossref","first-page":"G78","DOI":"10.1152\/ajpgi.00036.2003","article-title":"Regulation of the epithelial Ca2+ channels in small intestine as studied by quantitative mRNA detection","volume":"285","author":"van Abel","year":"2003","journal-title":"Am J Physiol Gastroinstest Liver Physiol"},{"key":"2024020319474603200_bib24","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1002\/jbmr.5650020617","article-title":"Bone histomorphometry: Standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee","volume":"2","author":"Parfitt","year":"1987","journal-title":"J Bone Miner Res"},{"key":"2024020319474603200_bib25","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.1359\/JBMR.050717","article-title":"Polymorphisms of the CLCN7 Gene Are Associated With BMD in Women","volume":"20","author":"Pettersson","year":"2005","journal-title":"J Bone Miner Res"},{"key":"2024020319474603200_bib26","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1016\/S0002-9440(10)63712-1","article-title":"Characterization of osteoclasts from patients harboring a G215R mutation in ClC-7 causing autosomal dominant osteopetrosis type II","volume":"164","author":"Henriksen","year":"2004","journal-title":"Am J Pathol"},{"key":"2024020319474603200_bib27","doi-asserted-by":"crossref","first-page":"3657","DOI":"10.1242\/jcs.112.21.3657","article-title":"Inhibition of intravacuolar acidification by antisense RNA decreases osteoclast differentiation and bone resorption in vitro","volume":"112","author":"Laitala-Leinonen","year":"1999","journal-title":"J Cell Sci"},{"key":"2024020319474603200_bib28","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1002\/jcb.10331","article-title":"Vitamin D and bone","volume":"88","author":"Suda","year":"2003","journal-title":"J Cell Biochem"},{"key":"2024020319474603200_bib29","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1677\/joe.0.1650163","article-title":"Effects of long-term administration of vitamin D3 analogs to mice","volume":"165","author":"Smith","year":"2000","journal-title":"J Endocrinol"},{"key":"2024020319474603200_bib30","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1002\/jbmr.5650050909","article-title":"Effects of (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate on mouse osteoclasts","volume":"5","author":"Marshall","year":"1990","journal-title":"J Bone Miner Res"},{"key":"2024020319474603200_bib31","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/0049-0172(94)90054-X","article-title":"Pamidronate stimulates recruitment and decreases longevity of osteoclast nuclei in mice","volume":"23","author":"Holt","year":"1994","journal-title":"Semin Arthritis Rheum"},{"key":"2024020319474603200_bib32","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/BF00675622","article-title":"Osteoclast recruitment in mice is stimulated by (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate","volume":"52","author":"Marshall","year":"1993","journal-title":"Calcif Tissue Int"},{"key":"2024020319474603200_bib33","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/S8756-3282(97)00006-9","article-title":"Effect of alendronate treatment on the osteoclastogenic potential of bone marrow cells in mice","volume":"20","author":"van Beek","year":"1997","journal-title":"Bone"},{"key":"2024020319474603200_bib34","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1002\/jbmr.5650050107","article-title":"Effects of bisphosphonates on isolated rat osteoclasts as examined by reflected light microscopy","volume":"5","author":"Sato","year":"1990","journal-title":"J Bone Miner Res"},{"key":"2024020319474603200_bib35","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1359\/jbmr.1998.13.11.1721","article-title":"Human osteoclast formation and activity in vitro: Effects of alendronate","volume":"13","author":"Breuil","year":"1998","journal-title":"J Bone Miner Res"},{"key":"2024020319474603200_bib36","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1007\/BF00298728","article-title":"Aminoalkylbisphosphonates, potent inhibitors of bone resorption, induce a prolonged stimulation of histamine synthesis and increase macrophages, granulocytes, and osteoclasts in vivo","volume":"52","author":"Endo","year":"1993","journal-title":"Calcif Tissue Int"},{"key":"2024020319474603200_bib37","first-page":"189","article-title":"Recent advances in osteoclast biology and pathological bone resorption","volume":"19","author":"Blair","year":"2004","journal-title":"Histol Histopathol"},{"key":"2024020319474603200_bib38","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1615\/CritRevEukarGeneExpr.v10.i3-4.10","article-title":"Regulation of differentiated osteoclasts","volume":"10","author":"Gay","year":"2000","journal-title":"Crit Rev Eukaryot Gene Expr"},{"key":"2024020319474603200_bib39","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1083\/jcb.111.3.1305","article-title":"Evidence for the presence of a proton pump of the vacuolar H+-ATPase type in the ruffled borders of osteoclasts","volume":"111","author":"Vaananen","year":"1990","journal-title":"J Cell Biol"},{"key":"2024020319474603200_bib40","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1006\/bbrc.1993.1551","article-title":"Effect of estrogen on acidification in osteoclasts","volume":"192","author":"Gay","year":"1993","journal-title":"Biochem Biophys Res Commun"},{"key":"2024020319474603200_bib41","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1172\/JCI115539","article-title":"Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure","volume":"88","author":"Sato","year":"1991","journal-title":"J Clin Invest"},{"key":"2024020319474603200_bib42","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1359\/jbmr.2000.15.6.1033","article-title":"Nuclear localization of the type 1 PTH\/PTHrP receptor in rat tissues","volume":"15","author":"Watson","year":"2000","journal-title":"J Bone Miner Res"},{"key":"2024020319474603200_bib43","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.steroids.2006.11.003","article-title":"Calcium uptake and membrane trafficking in response to PTH or 25(OH)D3 in polarized intestinal epithelial cells","volume":"72","author":"Sterling","year":"2007","journal-title":"Steroids"},{"key":"2024020319474603200_bib44","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1002\/jcb.10472","article-title":"Characterization of PTH\/PTHrP receptor in rat duodenum: Effects of ageing","volume":"88","author":"Gentili","year":"2003","journal-title":"J Cell Biochem"},{"key":"2024020319474603200_bib45","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1002\/jcb.10199","article-title":"Does PTH have a direct effect on intestine?","volume":"86","author":"Nemere","year":"2002","journal-title":"J Cell Biochem"},{"key":"2024020319474603200_bib46","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/S0002-9440(10)62269-9","article-title":"Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorption","volume":"166","author":"Karsdal","year":"2005","journal-title":"Am J Pathol"},{"key":"2024020319474603200_bib47","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/S8756-3282(99)00210-0","article-title":"Osteoblasts\/stromal cells stimulate osteoclast activation through expression of osteoclast differentiation factor\/RANKL but not macrophage colony-stimulating factor: Receptor activator of NF-kappa B ligand","volume":"25","author":"Udagawa","year":"1999","journal-title":"Bone"},{"key":"2024020319474603200_bib48","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.molmed.2004.12.004","article-title":"Osteoclast-derived activity in the coupling of bone formation to resorption","volume":"11","author":"Martin","year":"2005","journal-title":"Trends Mol Med"},{"key":"2024020319474603200_bib49","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1002\/jcb.240560312","article-title":"Mechanisms by which cells of the osteoblast lineage control osteoclast formation and activity","volume":"56","author":"Martin","year":"1994","journal-title":"J Cell Biochem"},{"key":"2024020319474603200_bib50","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/S1065-6995(03)00037-4","article-title":"The expression of matrix metalloproteinase-13 and osteocalcin in mouse osteoblasts is related to osteoblastic differentiation and is modulated by 1,25-dihydroxyvitamin-D3 and thyroid hormones","volume":"27","author":"Fratzl-Zelman","year":"2003","journal-title":"Cell Biol Int"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1359%2Fjbmr.080613","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/23\/11\/1815\/56569761\/5650231112.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/23\/11\/1815\/56569761\/5650231112.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T14:51:10Z","timestamp":1710341470000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/23\/11\/1815-1824\/7599380"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,11,1]]},"references-count":50,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2009,12,4]]},"published-print":{"date-parts":[[2008,11,1]]}},"URL":"https:\/\/doi.org\/10.1359\/jbmr.080613","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2008,11,1]]},"published":{"date-parts":[[2008,11,1]]}}}