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But, no study has yet demonstrated the effects of excess continuous PTH exposure, such as that seen in hyperparathyroidism, for fracture healing. Continuous human PTH<jats:sub>1\u201334<\/jats:sub> (teriparatide) infusion using an osmotic pump was performed for stabilized tibial fractures in eight-week-old male mice to determine the relative bone healing process compared with saline treatment. Radiographs and micro-computed tomography showed delayed but increased calcified callus formation in the continuous PTH<jats:sub>1\u201334<\/jats:sub> infusion group compared with the controls. Histology and quantitative histomorphometry confirmed that continuous PTH<jats:sub>1\u201334<\/jats:sub> treatment significantly increased the bone callus area at a later time point after fracture, since delayed endochondral ossification occurred. Gene expression analyses showed that PTH<jats:sub>1\u201334<\/jats:sub> resulted in sustained <jats:italic>Col2a1<\/jats:italic> and reduced <jats:italic>Col10a1<\/jats:italic> expression, consistent with delayed maturation of the cartilage tissue during fracture healing. In contrast, continuous PTH<jats:sub>1\u201334<\/jats:sub> infusion stimulated the expression of both <jats:italic>Bglap<\/jats:italic> and <jats:italic>Acp5<\/jats:italic> through the healing process, in accordance with bone callus formation and remodeling. Mechanical testing showed that continuously administered PTH<jats:sub>1\u201334<\/jats:sub> increased the maximum load on Day 21 compared with control mice. We concluded that continuous PTH<jats:sub>1\u201334<\/jats:sub> infusion resulted in a delayed fracture healing process due to delayed callus cell maturation but ultimately increased biomechanical properties.<\/jats:p>","DOI":"10.1038\/s41598-018-31345-1","type":"journal-article","created":{"date-parts":[[2018,8,29]],"date-time":"2018-08-29T15:48:35Z","timestamp":1535557715000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Continuous infusion of PTH1\u201334 delayed fracture healing in mice"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0040-1352","authenticated-orcid":false,"given":"Kiminori","family":"Yukata","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsukasa","family":"Kanchiku","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Egawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michihiro","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norihiro","family":"Nishida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyoshi","family":"Ogasa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihiko","family":"Taguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natsuo","family":"Yasui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,9,4]]},"reference":[{"key":"31345_CR1","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1073\/pnas.95.4.1387","volume":"95","author":"HL Brenza","year":"1998","unstructured":"Brenza, H. 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