Vitamin D Supplementation Enhances the Fixation of Titanium Implants in Chronic Kidney Disease Mice
Identifieur interne : 000750 ( Pmc/Corpus ); précédent : 000749; suivant : 000751Vitamin D Supplementation Enhances the Fixation of Titanium Implants in Chronic Kidney Disease Mice
Auteurs : Weiqing Liu ; Shiwen Zhang ; Dan Zhao ; Huawei Zou ; Ningyuan Sun ; Xing Liang ; Michel Dard ; Beate Lanske ; Quan YuanSource :
- PLoS ONE [ 1932-6203 ] ; 2014.
Abstract
Vitamin D (Vit D) deficiency is a common condition in chronic kidney disease (CKD) patients that negatively affects bone regeneration and fracture healing. Previous study has shown that timely healing of titanium implants is impaired in CKD. This study aimed to investigate the effect of Vit D supplementation on implant osseointegration in CKD mice. Uremia was induced by 5/6 nephrectomy in C57BL mice. Eight weeks after the second renal surgery, animals were given 1,25(OH)2D3 three times a week intraperitoneally for four weeks. Experimental titanium implants were inserted into the distal end of femurs two weeks later. Serum measurements confirmed decreased 1,25(OH)2D levels in CKD mice, which could be successfully corrected by Vit D injections. Moreover, the hyperparathyroidism observed in CKD mice was also corrected. X-ray examination and histological sections showed successful osseointegration in these mice. Histomorphometrical analysis revealed that the bone-implant contact (BIC) ratio and bone volume (BV/TV) around the implant were significantly increased in the Vit D-supplementation group. In addition, resistance of the implant, as measured by a push-in method, was significantly improved compared to that in the vehicle group. These results demonstrate that Vit D supplementation is an effective approach to improve the fixation of titanium implants in CKD.
Url:
DOI: 10.1371/journal.pone.0095689
PubMed: 24752599
PubMed Central: 3994107
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Vitamin D Supplementation Enhances the Fixation of Titanium Implants in Chronic Kidney Disease Mice</title><author><name sortKey="Liu, Weiqing" sort="Liu, Weiqing" uniqKey="Liu W" first="Weiqing" last="Liu">Weiqing Liu</name><affiliation><nlm:aff id="aff1"><addr-line>State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China</addr-line></nlm:aff></affiliation></author><author><name sortKey="Zhang, Shiwen" sort="Zhang, Shiwen" uniqKey="Zhang S" first="Shiwen" last="Zhang">Shiwen Zhang</name><affiliation><nlm:aff id="aff1"><addr-line>State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China</addr-line></nlm:aff></affiliation></author><author><name sortKey="Zhao, Dan" sort="Zhao, Dan" uniqKey="Zhao D" first="Dan" last="Zhao">Dan Zhao</name><affiliation><nlm:aff id="aff1"><addr-line>State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China</addr-line></nlm:aff></affiliation></author><author><name sortKey="Zou, Huawei" sort="Zou, Huawei" uniqKey="Zou H" first="Huawei" last="Zou">Huawei Zou</name><affiliation><nlm:aff id="aff1"><addr-line>State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sun, Ningyuan" sort="Sun, Ningyuan" uniqKey="Sun N" first="Ningyuan" last="Sun">Ningyuan Sun</name><affiliation><nlm:aff id="aff1"><addr-line>State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China</addr-line></nlm:aff></affiliation></author><author><name sortKey="Liang, Xing" sort="Liang, Xing" uniqKey="Liang X" first="Xing" last="Liang">Xing Liang</name><affiliation><nlm:aff id="aff1"><addr-line>State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dard, Michel" sort="Dard, Michel" uniqKey="Dard M" first="Michel" last="Dard">Michel Dard</name><affiliation><nlm:aff id="aff2"><addr-line>Department of Periodontology and Implant Dentistry, New York University College of Dentistry, New York, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lanske, Beate" sort="Lanske, Beate" uniqKey="Lanske B" first="Beate" last="Lanske">Beate Lanske</name><affiliation><nlm:aff id="aff3"><addr-line>Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental medicine, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Yuan, Quan" sort="Yuan, Quan" uniqKey="Yuan Q" first="Quan" last="Yuan">Quan Yuan</name><affiliation><nlm:aff id="aff1"><addr-line>State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24752599</idno><idno type="pmc">3994107</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994107</idno><idno type="RBID">PMC:3994107</idno><idno type="doi">10.1371/journal.pone.0095689</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">000750</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000750</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Vitamin D Supplementation Enhances the Fixation of Titanium Implants in Chronic Kidney Disease Mice</title><author><name sortKey="Liu, Weiqing" sort="Liu, Weiqing" uniqKey="Liu W" first="Weiqing" last="Liu">Weiqing Liu</name><affiliation><nlm:aff id="aff1"><addr-line>State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China</addr-line></nlm:aff></affiliation></author><author><name sortKey="Zhang, Shiwen" sort="Zhang, Shiwen" uniqKey="Zhang S" first="Shiwen" last="Zhang">Shiwen Zhang</name><affiliation><nlm:aff id="aff1"><addr-line>State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China</addr-line></nlm:aff></affiliation></author><author><name sortKey="Zhao, Dan" sort="Zhao, Dan" uniqKey="Zhao D" first="Dan" last="Zhao">Dan Zhao</name><affiliation><nlm:aff id="aff1"><addr-line>State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China</addr-line></nlm:aff></affiliation></author><author><name sortKey="Zou, Huawei" sort="Zou, Huawei" uniqKey="Zou H" first="Huawei" last="Zou">Huawei Zou</name><affiliation><nlm:aff id="aff1"><addr-line>State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sun, Ningyuan" sort="Sun, Ningyuan" uniqKey="Sun N" first="Ningyuan" last="Sun">Ningyuan Sun</name><affiliation><nlm:aff id="aff1"><addr-line>State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China</addr-line></nlm:aff></affiliation></author><author><name sortKey="Liang, Xing" sort="Liang, Xing" uniqKey="Liang X" first="Xing" last="Liang">Xing Liang</name><affiliation><nlm:aff id="aff1"><addr-line>State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dard, Michel" sort="Dard, Michel" uniqKey="Dard M" first="Michel" last="Dard">Michel Dard</name><affiliation><nlm:aff id="aff2"><addr-line>Department of Periodontology and Implant Dentistry, New York University College of Dentistry, New York, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lanske, Beate" sort="Lanske, Beate" uniqKey="Lanske B" first="Beate" last="Lanske">Beate Lanske</name><affiliation><nlm:aff id="aff3"><addr-line>Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental medicine, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Yuan, Quan" sort="Yuan, Quan" uniqKey="Yuan Q" first="Quan" last="Yuan">Quan Yuan</name><affiliation><nlm:aff id="aff1"><addr-line>State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Vitamin D (Vit D) deficiency is a common condition in chronic kidney disease (CKD) patients that negatively affects bone regeneration and fracture healing. Previous study has shown that timely healing of titanium implants is impaired in CKD. This study aimed to investigate the effect of Vit D supplementation on implant osseointegration in CKD mice. Uremia was induced by 5/6 nephrectomy in C57BL mice. Eight weeks after the second renal surgery, animals were given 1,25(OH)<sub>2</sub>D<sub>3</sub> three times a week intraperitoneally for four weeks. Experimental titanium implants were inserted into the distal end of femurs two weeks later. Serum measurements confirmed decreased 1,25(OH)<sub>2</sub>D levels in CKD mice, which could be successfully corrected by Vit D injections. Moreover, the hyperparathyroidism observed in CKD mice was also corrected. X-ray examination and histological sections showed successful osseointegration in these mice. Histomorphometrical analysis revealed that the bone-implant contact (BIC) ratio and bone volume (BV/TV) around the implant were significantly increased in the Vit D-supplementation group. In addition, resistance of the implant, as measured by a push-in method, was significantly improved compared to that in the vehicle group. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24752599</article-id><article-id pub-id-type="pmc">3994107</article-id><article-id pub-id-type="publisher-id">PONE-D-13-44576</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0095689</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Biology and Life Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Biological Tissue</subject><subj-group><subject>Connective Tissue</subject><subj-group><subject>Bone</subject></subj-group></subj-group></subj-group><subj-group><subject>Musculoskeletal System</subject></subj-group></subj-group><subj-group><subject>Biochemistry</subject><subj-group><subject>Metabolism</subject><subj-group><subject>Bone and Mineral Metabolism</subject></subj-group></subj-group></subj-group><subj-group><subject>Nutrition</subject><subj-group><subject>Nutrients</subject><subj-group><subject>Vitamins</subject></subj-group></subj-group><subj-group><subject>Nutritional Deficiencies</subject><subj-group><subject>Micronutrient Deficiencies</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Medicine and Health Sciences</subject><subj-group><subject>Nephrology</subject><subj-group><subject>Chronic Kidney Disease</subject><subject>Mineral Metabolism and the Kidney</subject></subj-group></subj-group><subj-group><subject>Oral Medicine</subject><subj-group><subject>Dentistry</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Research and Analysis Methods</subject><subj-group><subject>Model Organisms</subject><subj-group><subject>Animal Models</subject><subj-group><subject>Mouse Models</subject></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Vitamin D Supplementation Enhances the Fixation of Titanium Implants in Chronic Kidney Disease Mice</article-title><alt-title alt-title-type="running-head">Vit D Enhances Implant Fixation in CKD</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Weiqing</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Shiwen</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zhao</surname><given-names>Dan</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zou</surname><given-names>Huawei</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sun</surname><given-names>Ningyuan</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Liang</surname><given-names>Xing</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dard</surname><given-names>Michel</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lanske</surname><given-names>Beate</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Yuan</surname><given-names>Quan</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Department of Periodontology and Implant Dentistry, New York University College of Dentistry, New York, United States of America</addr-line></aff><aff id="aff3"><label>3</label><addr-line>Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental medicine, Boston, Massachusetts, United States of America</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Burdmann</surname><given-names>Emmanuel A.</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>University of Sao Paulo Medical School, Brazil</addr-line></aff><author-notes><corresp id="cor1">* E-mail: <email>yuanquan@scu.edu.cn</email></corresp><fn fn-type="conflict"><p><bold>Competing Interests: </bold>The authors have declared that no competing interests exist.</p></fn><fn fn-type="con"><p>Conceived and designed the experiments: QY BL MD. Performed the experiments: WL SZ DZ HZ NS. Analyzed the data: WL XL QY. Contributed reagents/materials/analysis tools: MD BL. Wrote the paper: WL BL QY.</p></fn></author-notes><pub-date pub-type="collection"><year>2014</year></pub-date><pub-date pub-type="epub"><day>21</day><month>4</month><year>2014</year></pub-date><pub-date pub-type="ecorrected"><day>21</day><month>5</month><year>2014</year></pub-date><volume>9</volume><issue>4</issue><elocation-id>e95689</elocation-id><history><date date-type="received"><day>31</day><month>10</month><year>2013</year></date><date date-type="accepted"><day>30</day><month>3</month><year>2014</year></date></history><permissions><copyright-year>2014</copyright-year><copyright-holder>Liu et al</copyright-holder><license><license-p>This is an open-access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><abstract><p>Vitamin D (Vit D) deficiency is a common condition in chronic kidney disease (CKD) patients that negatively affects bone regeneration and fracture healing. Previous study has shown that timely healing of titanium implants is impaired in CKD. This study aimed to investigate the effect of Vit D supplementation on implant osseointegration in CKD mice. Uremia was induced by 5/6 nephrectomy in C57BL mice. Eight weeks after the second renal surgery, animals were given 1,25(OH)<sub>2</sub>D<sub>3</sub> three times a week intraperitoneally for four weeks. Experimental titanium implants were inserted into the distal end of femurs two weeks later. Serum measurements confirmed decreased 1,25(OH)<sub>2</sub>D levels in CKD mice, which could be successfully corrected by Vit D injections. Moreover, the hyperparathyroidism observed in CKD mice was also corrected. X-ray examination and histological sections showed successful osseointegration in these mice. Histomorphometrical analysis revealed that the bone-implant contact (BIC) ratio and bone volume (BV/TV) around the implant were significantly increased in the Vit D-supplementation group. In addition, resistance of the implant, as measured by a push-in method, was significantly improved compared to that in the vehicle group. These results demonstrate that Vit D supplementation is an effective approach to improve the fixation of titanium implants in CKD.</p></abstract><funding-group><funding-statement>This work was supported by grants from the National Natural Science Foundation of China (NSFC 81371173), New Century Excellent Talents in University (NCET-12-0379) and International Team of Implantology (ITI 717_2010) to Q.Y., and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, R01-073944) to B.L. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement></funding-group><counts><page-count count="6"></page-count></counts></article-meta></front><body><sec id="s1"><title>Introduction</title><p>Chronic kidney disease (CKD) is recognized as a global public health threat. It is a highly prevalent disease with severe complications, such as cardiovascular disease and chronic kidney disease-mineral and bone disorders (CKD-MBD) <xref rid="pone.0095689-Moe1" ref-type="bibr">[1]</xref>–<xref rid="pone.0095689-Levey1" ref-type="bibr">[3]</xref>. Screening conducted by nephrologists from all over the world indicates that the incidence of CKD is increasing with ranges of 10.2% to 20% of the population <xref rid="pone.0095689-Saran1" ref-type="bibr">[4]</xref>–<xref rid="pone.0095689-Coresh2" ref-type="bibr">[7]</xref>. According to a recent cross-sectional survey in China, the prevalence of CKD adults was 10.8%, which means that approximately 119.5 million people are affected by CKD in this rapidly developing country <xref rid="pone.0095689-Zhang1" ref-type="bibr">[8]</xref>.</p><p>Declining renal function negatively affects the status of oral health. A recent systematic review showed that poor oral health is a common and often severe side-effect for adults with CKD <xref rid="pone.0095689-Ruospo1" ref-type="bibr">[9]</xref>. Approximately 90% of CKD patients suffer from oral symptoms,including both hard and soft tissues <xref rid="pone.0095689-JoverCervero1" ref-type="bibr">[10]</xref>–<xref rid="pone.0095689-Davidovich2" ref-type="bibr">[14]</xref>. Studies have demonstrated that CKD profoundly influences bone remolding <xref rid="pone.0095689-Kelly1" ref-type="bibr">[15]</xref> and the structure of the mandible <xref rid="pone.0095689-Lee1" ref-type="bibr">[16]</xref>. Furthermore, cross-sectional radiographic examinations indicate that CKD patients experience much more severe alveolar bone loss <xref rid="pone.0095689-Messier1" ref-type="bibr">[17]</xref>.</p><p>Although dental implants have been widely used in clinical settings, opinions regarding implants for CKD patients vary. Both the oral and nephrological literature suggests that dental implant surgery may be contraindicated in patients with significant renal osteodystrophy <xref rid="pone.0095689-Craig1" ref-type="bibr">[18]</xref>, <xref rid="pone.0095689-Stellingsma1" ref-type="bibr">[19]</xref>. However, other investigations into the quantity and quality of the alveolar bone of dialysis patients showed that the residual bone volumes were adequate for implant insertion, suggesting this type of treatment is applicable to CKD patients <xref rid="pone.0095689-Dijakiewicz1" ref-type="bibr">[20]</xref>. Previously, we studied the effect of CKD on osseointegration of titanium implants using a uremic mouse model. Although all implants were able to be successfully integrated, CKD significantly decreased the bone-implant strength at an early stage in healing <xref rid="pone.0095689-Zou1" ref-type="bibr">[21]</xref>. Therefore, enhancement of dental implant osseointegration in CKD patients remains a challenge.</p><p>Vitamin D deficiency is common in CKD patients <xref rid="pone.0095689-Ishimura1" ref-type="bibr">[22]</xref>–<xref rid="pone.0095689-LaClair1" ref-type="bibr">[26]</xref> and this deficiency may negatively affect bone regeneration and fracture healing due to its importance in bone metabolism <xref rid="pone.0095689-Brinker1" ref-type="bibr">[27]</xref>. Low serum 1,25-dihydroxyvitamin D triggers higher levels of serum PTH <xref rid="pone.0095689-Lips1" ref-type="bibr">[28]</xref>, <xref rid="pone.0095689-Bergwitz1" ref-type="bibr">[29]</xref>, which in turn promotes high bone turnover, exacerbates osteopenia and finally results in cortical bone loss and pathogenesis of osteoporosis <xref rid="pone.0095689-Andress1" ref-type="bibr">[30]</xref>–<xref rid="pone.0095689-Nickolas1" ref-type="bibr">[32]</xref>. Kelly <italic>et al</italic>. <xref rid="pone.0095689-Kelly1" ref-type="bibr">[15]</xref> showed that vitamin D insufficiency impairs the osseointegration of Ti6Al4V implants in male Sprague-Dawley rats. Alvim-Pereira F <italic>et al.</italic><xref rid="pone.0095689-AlvimPereira1" ref-type="bibr">[33]</xref> observed no association between a vitamin D receptor polymorphism (rs731236, TaqI) and dental implant loss. On the other hand, vitamin D supplementation has demonstrated a significant survival advantage in CKD patients <xref rid="pone.0095689-Chandra1" ref-type="bibr">[25]</xref>, and accelerated cellular events in the process of fracture healing <xref rid="pone.0095689-Jingushi1" ref-type="bibr">[34]</xref>. These findings suggest a potentially beneficial role for vitamin D in promoting implant osseointegration in CKD patients. In this study, we established a CKD mouse model to investigate the effect of vitamin D supplementation on fixation of titanium implants. The results are expected to be a significant contribution to dental implant therapy in CKD patients.</p></sec><sec sec-type="materials|methods" id="s2"><title>Materials and Methods</title><sec id="s2a"><title>Ethics Statement</title><p>This study was carried out in strict accordance with the recommendations contained in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and the ARRIVE guidelines (<ext-link ext-link-type="uri" xlink:href="http://www.nc3rs.org/ARRIVE">http://www.nc3rs.org/ARRIVE</ext-link>). All of the experiments performed were approved by the Subcommittee on Research and Animal Care (SRAC), which serves as the Institutional Animal Care and Use Committee (IACUC) at the Harvard Medical School (protocol number: 03901). All surgery was performed under anesthesia by intraperitoneal injection of a combination of ketamine (100 mg/ml) and xylazine (10 mg/ml), in addition, buprenorphine (0.05 mg/kg) was given for perioperative analgesia to minimize suffering and pain.</p></sec><sec id="s2b"><title>Animals</title><p>Thirty 9-week-old female C57BL mice (body weight: 22.0+2.0 g) were obtained from Charles River Laboratories International Inc. (Wilmington, MA) and randomly assigned to three groups: control(n = 10), CKD(n = 10), and CKD+Vit D(n = 10). The animals were kept under climate-controlled conditions (25°C; 55% humidity; 12 hours of light alternating with 12 hours of darkness) and fed with a standard diet. The workflow is illustrated in <xref ref-type="fig" rid="pone-0095689-g001">Figure 1</xref>.</p><fig id="pone-0095689-g001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0095689.g001</object-id><label>Figure 1</label><caption><title>Illustration of the workflow.</title><p>1<bold><sup>st</sup></bold> renal surgery: electrocautery of the left kidney; 2<sup>nd</sup> renal surgery: a total nephrectomy of the right kidney; Vitamin D injections started at 9<sup>th</sup> week (100ng/kg body weight, 3 times a week for 4 weeks).</p></caption><graphic xlink:href="pone.0095689.g001"></graphic></fig></sec><sec id="s2c"><title>Surgical Procedure to Induce Uremia</title><p>CKD is induced in mice by a two-step 5/6 nephrectomy to produce uremia as described previously <xref rid="pone.0095689-Zou1" ref-type="bibr">[21]</xref>. Briefly, the first procedure involves electrocautery of the left kidney except for a 2-mm area around the hilum. After 1 week, a total nephrectomy of the right kidney is performed by ligation of the renal hilum and surgical excision. Sham surgery consists of anesthetic administration, flank incision exposing the kidney, and closure of the abdominal wall.</p></sec><sec id="s2d"><title>Supplement of Active Vitamin D</title><p>The active form of vitamin D [1,25(OH)<sub>2</sub>D<sub>3</sub>], was obtained from Enzo Life Sciences Inc. (Farmingdale, NY) and diluted in saline. Eight weeks after the second kidney surgery, mice in the Vit D-treated group were injected with Vit D (100 ng/kg body weight) 3 times a week until they were sacrificed. Saline was used as a vehicle. The workflow is shown in Fig. S1.</p></sec><sec id="s2e"><title>Implant Surgery</title><p>Ten weeks after the second surgery (renal ablation), the mice were subjected to implant placement using the method described by Xu <italic>et al</italic>. <xref rid="pone.0095689-Xu1" ref-type="bibr">[35]</xref>. Titanium implants with SLA surface (1 mm in diameter and 4 mm in length) were obtained from Institut Straumann AG (Basel, Switzerland). They were cut to the length of 2 mm before insertion. After careful exposure of the distal aspects of the femurs via skin incision and muscle dissection, implant sites were prepared on both sides of the anterior-distal surfaces of the femurs by sequential drilling under cooled sterile saline irrigation with 0.7- and 1.0-mm surgical stainless steel twist drills. Then, the implants were press-fitted into the holes to reach primary stability. After the insertion of the implant, the muscles were carefully sutured with 6-0 silk, which covered the implant and further guaranteed its protection in the biological environment. Then the skin was closed with 5-0 silk.</p></sec><sec id="s2f"><title>Serum Biochemical Assays</title><p>Two weeks after the insertion of titanium implants, the mice were euthanized by carbon dioxide inhalation. Prior to euthanasia, blood was collected by cheek pouch puncture. Serum biochemistry was performed using commercially available kits: blood urea nitrogen (BUN) (Roche Diagnostics, Indianapolis, IN); 1,25(OH)<sub>2</sub>D (Immunodiagnostic Systems Ltd., Fountain Hills, AZ); Calcium and Phosphate (Stanbio Laboratory, Boerne, TX). For the assay of serum ALP activity, the serum was diluted 25 times and measured using a SensoLyte <italic>p</italic>NPP Alkaline Phosphatase Assay Kit (AnaSpec Inc., Fremont, CA).</p></sec><sec id="s2g"><title>X-ray Examination and Histological Preparation</title><p>Two weeks after implant placement, one femur carrying an implant was harvested from each mouse and fixed in 10% buffered formalin for 1 week at 4°C. Specimens were exposed to X-ray (20 kV, 5 seconds), and then dehydrated and embedded in light-curing epoxy resin (TechnoVit 7200VLC, Hereaus Kulzer, Wehrheim, Germany). Embedded specimens were cut perpendicular to the longitudinal axis of the implants at a site 0.5 mm from its apical end. The specimens were then ground to a thickness of about 50 µm with a grinding system (Exakt Apparatebau, Norderstedt, Germany). Sections were stained with Stevenel’s blue and Van Gieson’s picro fuchsin stain, and observed by light microscopy.</p></sec><sec id="s2h"><title>Histomorphometric Measurement</title><p>Images of the implant and peri-implant bone tissues were digitized and histomorphometrically analyzed with NIH Image J (National Institutes of Health, USA). Bone-implant contact (BIC) was calculated as the linear percentage of direct bone-to-implant contact to the total surface of the implant. And the bone volume (BV/TV) in the circumferential zone within 100 µm of the implant surface was calculated. The following formulas were used for analysis.<disp-formula id="pone.0095689.e001"><graphic xlink:href="pone.0095689.e001.jpg" position="anchor" orientation="portrait"></graphic></disp-formula></p><p><disp-formula id="pone.0095689.e002"><graphic xlink:href="pone.0095689.e002.jpg" position="anchor" orientation="portrait"></graphic></disp-formula></p></sec><sec id="s2i"><title>Implant Biomechanical Push-in Test</title><p>The remaining femur from each mouse was harvested and embedded into auto-polymerizing resin with the top surface of the implant level. A test machine (AG-TA electronic universal testing machine, SHIMADZU, Japan) equipped with a pushing rod (diameter = 0.8 mm) was used to load the implant vertically downward at a crosshead speed of 1 mm/min. The push-in value was determined by measuring the peak of the load-displacement curve.</p></sec><sec id="s2j"><title>Statistical Analysis</title><p>All values were presented as mean ± SD. Statistically significant differences were assessed by ANOVA followed by Tukey’s test for multiple comparison, or by independent student <italic>t</italic> test for comparison between two groups. A <italic>p</italic> value of less than 0.05 was considered to be statistically significant.</p></sec></sec><sec id="s3"><title>Results</title><sec id="s3a"><title>Animals</title><p>As anticipated, all mice tolerated the surgical procedures well and survived the full experimental period. No inflammation or infection at the implant site was observed.</p></sec><sec id="s3b"><title>Serum Biochemistry</title><p>A significant increase in serum BUN was observed in the CKD (53.87±6.32) and CKD+Vit D (58.45±4.33) groups as compared to that of controls (20.12±3.46) (<italic>p</italic><0.05), indicating the successful establishment of the uremic mouse model (<xref ref-type="fig" rid="pone-0095689-g002">Figure 2A</xref>). Vit D injections did not cause a significant change in the serum BUN level. As shown in <xref ref-type="fig" rid="pone-0095689-g002">Figure 2B</xref>, Vit D was significantly decreased in the CKD group (27.51±8.35) (<italic>p</italic><0.05), while supplementing with Vit D (62.44±26.88) restored it to levels comparable to those in control mice (52.35±16.33). Serum PTH in the CKD group was 3.6-fold that observed in the control group (<italic>p</italic><0.05). It decreased to the levels comparable to the control upon Vit D treatment (<xref ref-type="fig" rid="pone-0095689-g002">Figure 2C</xref>). There was no significant difference in serum calcium (<xref ref-type="fig" rid="pone-0095689-g002">Figure 2D</xref>) and phosphate (<xref ref-type="fig" rid="pone-0095689-g002">Figure 2E</xref>) levels among the three groups. Serum ALP decreased significantly in the Vit D-treated group as compared to the CKD group (<italic>p</italic><0.05), although it was still significantly higher than that of control (<xref ref-type="fig" rid="pone-0095689-g002">Figure 2F</xref>).</p><fig id="pone-0095689-g002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0095689.g002</object-id><label>Figure 2</label><caption><title>Serum biochemical measurements.</title><p>(A) Serum BUN; (B) Serum Vitamin D; (C) Serum PTH; (D) Serum calcium; (E) Serum phosphate, and (F) Serum ALP activity. *: <italic>p</italic><0.05 <italic>vs</italic> Control; #: <italic>p</italic><0.05 <italic>vs</italic> CKD.</p></caption><graphic xlink:href="pone.0095689.g002"></graphic></fig></sec><sec id="s3c"><title>X-ray Examination</title><p>The <italic>ex vivo</italic> X-ray examination of the femurs showed that the implants were surrounded with bone without any notable radiotranslucent gap, indicating successful osseointegration in all groups (<xref ref-type="fig" rid="pone-0095689-g003">Figure 3</xref>).</p><fig id="pone-0095689-g003" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0095689.g003</object-id><label>Figure 3</label><caption><title>X-ray examination of the femurs after 2-weeks healing.</title><p>The implants were surrounded with bone without any notable radiotranslucent gap.</p></caption><graphic xlink:href="pone.0095689.g003"></graphic></fig></sec><sec id="s3d"><title>Histology and Histomorphometry</title><p>Examination of histological sections confirmed a direct bone-implant contact in all groups (<xref ref-type="fig" rid="pone-0095689-g004">Figure 4A</xref>). Consistent with our previous report <xref rid="pone.0095689-Zou1" ref-type="bibr">[21]</xref>, the CKD group showed a decrease of bone-implant contact ratio (BIC) when compared to that of control. The contact ratio was successfully restored to the normal level after Vit D treatment. As shown in <xref ref-type="fig" rid="pone-0095689-g004">Figure 4B</xref>, the BIC of CKD+VitD group was 75.23±9.92, over 20% higher than that of CKD mice (61.86±10.11) (<italic>p</italic><0.05). We then calculated the bone volume (BV/TV) in the circumferential zone within 100 µm of the implant surface and were able to observe a 35% increase after Vit D treatment (<xref ref-type="fig" rid="pone-0095689-g004">Figure 4C</xref>).</p><fig id="pone-0095689-g004" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0095689.g004</object-id><label>Figure 4</label><caption><title>Histological and histomorphometrical analysis of the implants after 2-week healing.</title><p>(A) Representative images of undecalified sections from all three groups; VitD injection significantly increased (B) Bone-implant contact ratio (BIC, %), and (C) bone volume (BV/TV) in the circumferential zone within 100 µm of the implant surface. *: <italic>p</italic><0.05 <italic>vs</italic> Control; #: <italic>p</italic><0.05 <italic>vs</italic> CKD.</p></caption><graphic xlink:href="pone.0095689.g004"></graphic></fig></sec><sec id="s3e"><title>The Resistance of Implant</title><p>In the early healing stage (week 2), the resistance of the implant was significantly higher for the Vit D treated group (15.21±4.11) compared to that of the untreated CKD mice (9.86±1.89), indicating an improved strength of bone–implant integration (<xref ref-type="fig" rid="pone-0095689-g005">Figure 5</xref>). No significant difference in integration was observed between the control and CKD+VitD groups.</p><fig id="pone-0095689-g005" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0095689.g005</object-id><label>Figure 5</label><caption><title>Resistance of push-in tests 2 weeks after implant placement.</title><p>Vit D supplementation corrected the resistance of implant in CKD. *: <italic>p</italic><0.05 <italic>vs</italic> control; #: <italic>p</italic><0.05 <italic>vs</italic> CKD.</p></caption><graphic xlink:href="pone.0095689.g005"></graphic></fig></sec></sec><sec id="s4"><title>Discussion</title><p>Vitamin D is a pleiotropic hormone that plays a critical role in regulating mineral ion metabolism <xref rid="pone.0095689-Lips1" ref-type="bibr">[28]</xref>. It is initially biologically inactive and requires sequential hydroxylations in the liver and kidney to produce its active form, 1,25-dihydroxyvitamin D <xref rid="pone.0095689-Lips1" ref-type="bibr">[28]</xref>. Vit D insufficiency is a common medical condition in CKD patients <xref rid="pone.0095689-Rouached1" ref-type="bibr">[24]</xref>, where declining renal function impairs the activity of 1-α hydroxylase (1α-OHase) in kidney, which in turn reduces its ability to convert 25(OH)<sub>2</sub>D to its activated form, 1,25(OH)<sub>2</sub>D. In this study, we established a uremic mouse model with significantly reduced levels of 1,25(OH)<sub>2</sub>D using the 5/6 nephrectomy method. These data are consistent with previous studies and similar to the clinical situation in CKD patients <xref rid="pone.0095689-Hasegawa1" ref-type="bibr">[36]</xref>, <xref rid="pone.0095689-Pillar1" ref-type="bibr">[37]</xref>.</p><p>Vitamin D deficiency negatively affects bone regeneration, including fracture healing, due to its importance in bone metabolism <xref rid="pone.0095689-Brinker1" ref-type="bibr">[27]</xref>. Moreover, Kelly <italic>et al</italic>. <xref rid="pone.0095689-Kelly1" ref-type="bibr">[15]</xref> showed that vitamin D insufficiency decreased the bone-implant contact ratio and the resistance in push-in tests. Recently, Choukroun <italic>et al</italic>. <xref rid="pone.0095689-Choukroun1" ref-type="bibr">[38]</xref> found that Vit D deficiency slows down the process of osseointegration, and also promotes infection in the graft. A genome-wide screening also suggested that Vit D deficiency affects the osseointegration of implants by regulating the circadian rhythm system and the cartilage extracellular matrix <xref rid="pone.0095689-Mengatto1" ref-type="bibr">[39]</xref>.</p><p>On the other hand, vitamin D supplementation has demonstrated a significant survival advantage in CKD patients <xref rid="pone.0095689-Chandra1" ref-type="bibr">[25]</xref>, including accelerated cellular events in the process of fracture healing <xref rid="pone.0095689-Jingushi1" ref-type="bibr">[34]</xref>. Vitamin D supplementation has been recommended as the primary therapy by the National Kidney Foundation to control secondary hyperparathyroidism and prevent skeletal complications in end stage renal failure patients <xref rid="pone.0095689-Eknoyan1" ref-type="bibr">[40]</xref>, <xref rid="pone.0095689-Andress2" ref-type="bibr">[41]</xref>. Two recent studies demonstrated that Vit D supplementation was able to enhance implant fixation in diabetic mellitus rats with Vit D insufficiency <xref rid="pone.0095689-Akhavan1" ref-type="bibr">[42]</xref>, <xref rid="pone.0095689-Wu1" ref-type="bibr">[43]</xref>. Similar results were reported in studies using normal <xref rid="pone.0095689-Cho1" ref-type="bibr">[44]</xref> or ovariectomized animals <xref rid="pone.0095689-Dvorak1" ref-type="bibr">[45]</xref>, <xref rid="pone.0095689-Zhou1" ref-type="bibr">[46]</xref>. In this study, we successfully corrected the decreased 1,25(OH)<sub>2</sub>D levels in CKD mice by Vit D injection, and found that both the bone-implant contact (BIC) ratio and the resistance of implant were significantly increased after a 2-week healing period, indicating that Vit D supplementation is an effective approach to improve fixation of titanium implants in CKD.</p><p>We also found that Vit D supplementation successfully corrected the increased levels of PTH, a key hormone for bone remodeling. In CKD patients, low serum 1,25-dihydroxyvitamin D triggers higher secretion of PTH <xref rid="pone.0095689-Lips1" ref-type="bibr">[28]</xref>, <xref rid="pone.0095689-Bergwitz1" ref-type="bibr">[29]</xref>, which precipitates high bone turnover and exacerbates osteopenia and finally results in bone loss <xref rid="pone.0095689-Andress1" ref-type="bibr">[30]</xref>–<xref rid="pone.0095689-Nickolas1" ref-type="bibr">[32]</xref>. A meta-analysis performed by Kandula <italic>et al</italic>. <xref rid="pone.0095689-Kandula1" ref-type="bibr">[47]</xref> showed that any form of vitamin D (including calcitriol or a vitamin D analog) lowers PTH levels in CKD patients. In this context, we hypothesize that in addition to the direct impact of Vit D on bone healing, the normalization of PTH levels might also contribute to the enhancement of implant fixation. However the direct effect of PTH on osseointegration in CKD needs to be studied further.</p><p>It should be noted that this study was performed using a mouse model with the implants placed in the distal end of femurs. Although the rodent model has been widely used for research in implant dentistry<xref rid="pone.0095689-Akhavan1" ref-type="bibr">[42]</xref>, <xref rid="pone.0095689-Dvorak1" ref-type="bibr">[45]</xref>, <xref rid="pone.0095689-Zhou1" ref-type="bibr">[46]</xref>, the development and characterization of the femur is different from the jaw bone. A canine or mini pig model might be a better alternative as the implants can be inserted in the jaw bone instead of the femur. However, the establishment of CKD in these large animals is not yet well-established. Clinical trials are expected to confirm whether supplement of Vit D could be a good candidate for clinical approaches to enhance the fixation of titanium implants in CKD patients.</p></sec><sec id="s5"><title>Conclusion</title><p>In this study, we found that Vit D supplementation successfully restored serum 1,25(OH)<sub>2</sub>D levels and corrected the hyperparathyroidism in CKD mice. The bone-implant contact ratio, bone volume around implant and the resistance of the implant were improved at 2 weeks after implantation, indicating that Vit D supplementation is an effective approach to improve the fixation of titanium implants in CKD.</p></sec></body><back><ack><p>We thank Dr. Hans-Peter Weber, Department of Prosthodontics and Operative Dentistry, Tufts University School of Dental Medicine, for the discussion and advice for this study, and Michael Densmore, Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental medicine, for assistance in editing the manuscript.</p></ack><ref-list><title>References</title><ref id="pone.0095689-Moe1"><label>1</label><mixed-citation publication-type="journal"><name><surname>Moe</surname><given-names>S</given-names></name>, <name><surname>Drueke</surname><given-names>T</given-names></name>, <name><surname>Cunningham</surname><given-names>J</given-names></name>, <name><surname>Goodman</surname><given-names>W</given-names></name>, <name><surname>Martin</surname><given-names>K</given-names></name>, <etal>et al</etal> (<year>2006</year>) <article-title>Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO)</article-title>. <source>Kidney Int</source><volume>69</volume>: <fpage>1945</fpage>–<lpage>1953</lpage><pub-id pub-id-type="pmid">16641930</pub-id></mixed-citation></ref><ref id="pone.0095689-NationalKidney1"><label>2</label><mixed-citation publication-type="journal"><name><surname>National Kidney</surname><given-names>F</given-names></name> (<year>2003</year>) <article-title>K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease</article-title>. <source>American journal of kidney diseases : the official journal of the National Kidney Foundation</source><volume>42</volume>: <fpage>S1</fpage>–<lpage>201</lpage><pub-id pub-id-type="pmid">14520607</pub-id></mixed-citation></ref><ref id="pone.0095689-Levey1"><label>3</label><mixed-citation publication-type="journal"><name><surname>Levey</surname><given-names>AS</given-names></name>, <name><surname>Atkins</surname><given-names>R</given-names></name>, <name><surname>Coresh</surname><given-names>J</given-names></name>, <name><surname>Cohen</surname><given-names>EP</given-names></name>, <name><surname>Collins</surname><given-names>AJ</given-names></name>, <etal>et al</etal> (<year>2007</year>) <article-title>Chronic kidney disease as a global public health problem: approaches and initiatives - 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