{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T14:19:58Z","timestamp":1751465998466},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2010,6,30]],"date-time":"2010-06-30T00:00:00Z","timestamp":1277856000000},"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":[[2010,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The mechanisms that underlie growth plate chondrocyte volume increase and hence bone lengthening are poorly understood. Many cell types activate the Na-K-Cl cotransporter (NKCC) to bring about volume increase. We hypothesised that NKCC may be responsible for the volume expansion of hypertrophic chondrocytes. Metatarsals\/metacarpals from 16 rat pups (P7) were incubated in the presence\/absence of the specific NKCC inhibitor bumetanide and measurement of whole-bone lengths and histologic analysis of the growth plate were done after 24\u2009hours. Fluorescent NKCC immunohistochemistry was visualised using a confocal laser scanning microscopy on seven rat tibial growth plates (P7). Microarray analysis was performed on mRNA isolated from proliferative and hypertrophic zone cells of tibial growth plates from five rats of each of three ages (P49\/53\/58). Exposure to bumetanide resulted in approximately 35% reduction (paired Student's t test, p\u2009&amp;lt;\u2009.05) of bone growth in a dose-dependent manner; histologic analysis showed that a reduction in hypertrophic zone height was responsible. Quantification of fluorescence immunohistochemistry revealed a significant (paired Student's t test, p\u2009&amp;lt;\u2009.05) change in NKCC from the intracellular space of proliferative cells to the cytosolic membrane of hypertrophic zone cells. Further, microarray analysis illustrated an increase in NKCC1 mRNA between proliferative and hypertrophic cells. The increase in NKCC1 mRNA in hypertrophic zone cells, its cellular localization, and reduced bone growth in the presence of the NKCC inhibitor bumetanide implicate NKCC in growth plate hypertrophic chondrocyte volume increase. Further investigation is warranted to determine the regulatory control of NKCC in the mammalian growth plate and the possible detrimental effect on bone growth with chronic exposure to loop diuretics. \u00a9 2010 American Society for Bone and Mineral Research<\/jats:p>","DOI":"10.1002\/jbmr.47","type":"journal-article","created":{"date-parts":[[2010,1,29]],"date-time":"2010-01-29T18:37:52Z","timestamp":1264790272000},"page":"1594-1603","source":"Crossref","is-referenced-by-count":22,"title":["A key role for membrane transporter NKCC1 in mediating chondrocyte volume increase in the mammalian growth plate"],"prefix":"10.1093","volume":"25","author":[{"given":"Peter G","family":"Bush","sequence":"first","affiliation":[{"name":"Centre for Biomedical and Health Science Research, School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meredith","family":"Pritchard","sequence":"additional","affiliation":[{"name":"Musculoskeletal Sciences Research Laboratory, Department of Orthopedic Surgery, State University of New York Upstate Medical University, Syracuse, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamad Y","family":"Loqman","sequence":"additional","affiliation":[{"name":"Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, Scotland, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy A","family":"Damron","sequence":"additional","affiliation":[{"name":"Musculoskeletal Sciences Research Laboratory, Department of Orthopedic Surgery, State University of New York Upstate Medical University, Syracuse, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew C","family":"Hall","sequence":"additional","affiliation":[{"name":"Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, Scotland, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2010,6,30]]},"reference":[{"key":"2024020320131397100_bib1","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1002\/jor.1100140613","article-title":"Differential growth by growth plates as a function of multiple parameters of chondrocytic kinetics","volume":"14","author":"Wilsman","year":"1996","journal-title":"J Orthop Res."},{"key":"2024020320131397100_bib2","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1002\/jcp.21249","article-title":"The osmotic sensitivity of rat growth plate chondrocytes in situ: clarifying the mechanisms of hypertrophy","volume":"214","author":"Bush","year":"2008","journal-title":"J Cell Physiol."},{"key":"2024020320131397100_bib3","doi-asserted-by":"crossref","first-page":"243","DOI":"10.2106\/00004623-198668020-00010","article-title":"Morphometric analysis of chondrocyte hypertrophy","volume":"68A","author":"Buckwalter","year":"1986","journal-title":"J Bone Joint Surg."},{"key":"2024020320131397100_bib4","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1016\/0140-6736(93)90828-5","article-title":"Cellular hydration state: an important determinant of protein catabolism in health and disease","volume":"341","author":"Haussinger","year":"1993","journal-title":"Lancet."},{"key":"2024020320131397100_bib5","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/S8756-3282(01)00710-4","article-title":"Volume increase in growth plate chondrocytes during hypertrophy: the contribution of organic osmolytes","volume":"30","author":"Farnum","year":"2002","journal-title":"Bone."},{"key":"2024020320131397100_bib6","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1152\/physrev.1998.78.1.247","article-title":"Functional significance of cell volume regulatory mechanisms","volume":"78","author":"Lang","year":"1998","journal-title":"Physiol. 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