{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T07:04:40Z","timestamp":1761894280930},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[1998,6,1]],"date-time":"1998-06-01T00:00:00Z","timestamp":896659200000},"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":[[1998,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The role of hormonal status in the development of aluminum (Al)-dependent renal osteodystrophy, which is characterized by reduced bone matrix deposition, still remains largely unknown. To address this question, we used the osteoblast-like osteosarcoma cell line ROS 17\/2.8 to evaluate the role of Al on parathyroid hormone (PTH)- and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)-dependent activities in these cells. Al (1 \u03bcM) caused an inhibition of basal and 1,25(OH)2D3-induced alkaline phosphatase, but only at low doses (&amp;lt;1 nM) of the steroid. Al partly inhibited basal osteocalcin (OC) secretion in ROS cells (p &amp;lt; 0.001), and the dose-dependent increase in 1,25(OH)2D3-induced OC release by these cells was also reduced by 1 \u03bcM Al at low concentrations of the steroid (\u22641 nM), whereas high doses of 1,25(OH)2D3 (\u22655 nM) totally prevented the inhibiting effects of Al. Al also had strong inhibitory actions on PTH-dependent cAMP production by ROS cells over the concentration range tested (0.5\u201350 nM). This inhibitory action of Al was also observed for PTH-related peptide- (PTHrp, 50 nM) but not for Isoproterenol-dependent (100 nM) cAMP formation. To evaluate more fully the mechanism of this inhibition of cAMP formation, we investigated the effect of Al on toxin-modulated, G protein\u2013dependent regulation of cAMP formation and on the activation of adenylate cyclase by Forskolin. Cholera toxin (CT, 10 \u03bcg\/ml), applied to cells for 4 h prior to PTH challenge, enhanced cAMP production about 2-fold above PTH alone (p &amp;lt; 0.001), a process that was further stimulated by Al. Pertussis toxin (PT, 1 \u03bcg\/ml, 4 h) did not modify basal PTH-dependent cAMP formation by ROS cells. However, PT treatment prevented the inhibitory effect of Al on cAMP formation by these cells (p &amp;lt; 0.025). The stimulation of adenylate cyclase by Forskolin (0.1 and 1 \u03bcM), which bypasses G protein regulation, was not modified by Al, indicating that Al does not affect adenylate cyclase directly. Northern blot analysis of PTH receptor mRNA levels showed that Al did not modify PTH receptor message in ROS cells. Likewise, Western blot analyses of G protein subunits showed that Al did not significantly alter Gs \u03b1 subunit levels, in accordance with the results obtained for cAMP-dependent formation in response to CT. In contrast, Gi\u03b1-1 and Gi\u03b1-2 subunits were decreased by Al treatment, consistent with PT-restricted increases in cAMP formation in Al-treated ROS cells. Taken together, these results suggest that Al has multiple actions in osteoblast-like ROS cells. The effects of Al are modulated by hormonal control of the pathways investigated. Al affects 1,25(OH)2D3-regulated functions only when this steroid is low. Al has large inhibitory effects on PTH- and PTHrp-dependent cAMP formation. This last feature is related to the ability of Al to alter the G protein transducing pathway for PTH\/PTHrp-dependent formation of cAMP since it does not affect adenylate cyclase activity directly and does not affect the PTH receptor message level. Thus, Al has stronger deleterious effects in osteoblast-like cells with an already compromised 1,25(OH)2D3 status and can modulate specifically PTH\/PTHrp-mediated cAMP formation at the postreceptor level.<\/jats:p>","DOI":"10.1359\/jbmr.1998.13.6.962","type":"journal-article","created":{"date-parts":[[2006,4,26]],"date-time":"2006-04-26T23:44:02Z","timestamp":1146095042000},"page":"962-969","source":"Crossref","is-referenced-by-count":10,"title":["Influence of Aluminum on the Regulation of PTH- and 1,25(OH)2D3-Dependent Pathways in the Rat Osteosarcoma Cell Line ROS 17\/2.8"],"prefix":"10.1093","volume":"13","author":[{"given":"D.","family":"Lajeunesse","sequence":"first","affiliation":[{"name":"Centre de Recherche L.C. Simard, C.H.U.M., Pavillon Notre-Dame, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R.","family":"Moreau","sequence":"additional","affiliation":[{"name":"Centre de Recherche Guy-Bernier, H\u00f4pital Maisonneuve-Rosemont, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W.","family":"Hobbs","sequence":"additional","affiliation":[{"name":"Department of Medicine, Johns Hopkins Medical School, Baltimore, Maryland, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W.","family":"Qui","sequence":"additional","affiliation":[{"name":"Department of Medicine, Johns Hopkins Medical School, Baltimore, Maryland, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J.","family":"Lafond","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Biologie, Universit\u00e9 du Qu\u00e9bec \u00e0 Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. E.","family":"Guggino","sequence":"additional","affiliation":[{"name":"Department of Medicine, Johns Hopkins Medical School, Baltimore, Maryland, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2009,12,4]]},"reference":[{"key":"2024020713285020700_bib1","first-page":"3035","volume-title":"Diseases of the Kidney","author":"Sherrard","year":"1988"},{"key":"2024020713285020700_bib2","doi-asserted-by":"crossref","first-page":"161","DOI":"10.7326\/0003-4819-80-2-161","article-title":"1,25 dihydroxyvitamin D3 in normal man and patients with renal failure","volume":"80","author":"Brickman","year":"1974","journal-title":"Ann Intern Med"},{"key":"2024020713285020700_bib3","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1152\/physrev.1989.69.3.990","article-title":"Osteocalcin and matrix Gla protein: Vitamin K-dependent proteins in bone","volume":"69","author":"Hauschka","year":"1989","journal-title":"Physiol 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