{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T10:09:38Z","timestamp":1773482978993,"version":"3.50.1"},"reference-count":51,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2014,9,29]],"date-time":"2014-09-29T00:00:00Z","timestamp":1411948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The objective of this study was to investigate whether intermittent administration of parathyroid hormone [1\u201334] (PTH[1\u201334]) promotes tendon-bone healing after anterior cruciate ligament (ACL) reconstruction in vivo. A rat model of ACL reconstruction with autograft was established at the left hind leg. Every day, injections of 60 \u03bcg PTH[1\u201334]\/kg subcutaneously were given to the PTH group rats (n = 10) for four weeks, and the controls (n = 10) received saline. The tendon-bone healing process was evaluated by micro-CT, biomechanical test, histological and immunohistochemical analyses. The effects of PTH[1\u201334] on serum chemistry, bone microarchitecture and expression of the PTH receptor (PTH1R) and osteocalcin were determined. Administration of PTH[1\u201334] significantly increased serum levels of calcium, alkaline phosphatase (AP), osteocalcin and tartrate-resistant acid phosphatase (TRAP). The expression of PTH1R on both osteocytes and chondrocyte-like cells at the tendon-bone interface was increased in the PTH group. PTH[1\u201334] also enhanced the thickness and microarchitecture of trabecular bone according to the micro-CT analysis. The results imply that systematically intermittent administration of PTH[1\u201334] promotes tendon-bone healing at an early stage via up-regulated PTH1R. This method may enable a new strategy for the promotion of tendon-bone healing after ACL reconstruction.<\/jats:p>","DOI":"10.3390\/ijms151017366","type":"journal-article","created":{"date-parts":[[2014,9,29]],"date-time":"2014-09-29T11:16:45Z","timestamp":1411989405000},"page":"17366-17379","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Intermittently Administered Parathyroid Hormone [1\u201334] Promotes Tendon-Bone Healing in a Rat Model"],"prefix":"10.3390","volume":"15","author":[{"given":"Fanggang","family":"Bi","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhongli","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuai","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigui","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2014,9,29]]},"reference":[{"key":"ref_1","first-page":"463","article-title":"Evaluation and treatment of recurrent instability after anterior cruciate ligament reconstruction","volume":"50","author":"Harner","year":"2001","journal-title":"Instr. Course Lect."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1016\/j.arthro.2011.02.015","article-title":"Comparison of the clinical outcome of double-bundle, anteromedial single-bundle, and posterolateral single-bundle anterior cruciate ligament reconstruction using hamstring tendon graft with minimum 2-year follow-up","volume":"27","author":"Fujita","year":"2011","journal-title":"Arthroscopy"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.arthro.2006.08.008","article-title":"Double-bundle \u201canatomic\u201d anterior cruciate ligament reconstruction: A cadaveric study of tunnel positioning with a transtibial technique","volume":"23","author":"Giron","year":"2007","journal-title":"Arthroscopy"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1177\/0363546508314428","article-title":"Primary anatomic double-bundle anterior cruciate ligament reconstruction: A preliminary 2-year prospective study","volume":"36","author":"Fu","year":"2008","journal-title":"Am. J. Sports Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1053\/jars.2001.24059","article-title":"Comparisons of intraosseous graft healing between the doubled flexor tendon graft and the bone-patellar tendon-bone graft in anterior cruciate ligament reconstruction","volume":"17","author":"Tomita","year":"2001","journal-title":"Arthroscopy"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s002640000199","article-title":"A comparative study of the healing of tendon autograft and tendon-bone autograft using patellar tendon in rabbits","volume":"25","author":"Park","year":"2001","journal-title":"Int. Orthop."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1177\/03635465010290051501","article-title":"A multidisciplinary study of the healing of an intraarticular anterior cruciate ligament graft in a goat model","volume":"29","author":"Papageorgiou","year":"2001","journal-title":"Am. J. Sports Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1177\/03635465990270041201","article-title":"Use of recombinant human bone morphogenetic protein-2 to enhance tendon healing in a bone tunnel","volume":"27","author":"Rodeo","year":"1999","journal-title":"Am. J. Sports Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1002\/jbm.b.30049","article-title":"Engineered allogeneic chondrocyte pellet for reconstruction of fibrocartilage zone at bone-tendon junction\u2014A preliminary histological observation","volume":"70","author":"Wong","year":"2004","journal-title":"J. Biomed. Mater. Res. B"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"13","DOI":"10.4161\/org.27404","article-title":"Cellular therapy in bone-tendon interface regeneration","volume":"10","author":"Rothrauff","year":"2014","journal-title":"Organogenesis"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1177\/0363546508314396","article-title":"Augmentation of tendon-to-bone healing with a magnesium-based bone adhesive","volume":"36","author":"Gulotta","year":"2008","journal-title":"Am. J. Sports Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1002\/jbmr.304","article-title":"PTH receptor signaling in osteocytes governs periosteal bone formation and intracortical remodeling","volume":"26","author":"Rhee","year":"2011","journal-title":"J. Bone Miner. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.injury.2011.03.061","article-title":"Systemic administration of pharmacological agents and bone repair: What can we expect","volume":"42","author":"Bukata","year":"2011","journal-title":"Injury"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/excr.2002.5580","article-title":"Four distinct chondrocyte populations in the fetal bovine growth plate: Highest expression levels of PTH\/PTHrP receptor, Indian hedgehog, and MMP-13 in hypertrophic chondrocytes and their suppression by PTH (1\u201334) and PTHrP (1\u201340)","volume":"279","author":"Weisser","year":"2002","journal-title":"Exp. Cell Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1016\/j.bone.2007.03.017","article-title":"Molecular and cellular mechanisms of the anabolic effect of intermittent PTH","volume":"40","author":"Jilka","year":"2007","journal-title":"Bone"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.bone.2013.02.023","article-title":"PTH prevents the adverse effects of focal radiation on bone architecture in young rats","volume":"55","author":"Chandra","year":"2013","journal-title":"Bone"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.tem.2004.01.006","article-title":"Parathyroid hormone: A double-edged sword for bone metabolism","volume":"15","author":"Qin","year":"2004","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.bone.2008.09.019","article-title":"Cancellous and cortical bone architecture and turnover at the iliac crest of postmenopausal osteoporotic women treated with parathyroid hormone 1\u201384","volume":"44","author":"Recker","year":"2009","journal-title":"Bone"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1359\/jbmr.2003.18.11.1932","article-title":"Recombinant human parathyroid hormone (1\u201334) [teriparatide] improves both cortical and cancellous bone structure","volume":"18","author":"Jiang","year":"2003","journal-title":"J. Bone Miner. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1177\/0363546506296312","article-title":"Bone morphogenetic proteins-signaling plays a role in tendon-to-bone healing: A study of rhBMP-2 and noggin","volume":"35","author":"Ma","year":"2007","journal-title":"Am. J. Sports Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1002\/jor.21301","article-title":"Sustained delivery of transforming growth factor beta three enhances tendon-to-bone healing in a rat model","volume":"29","author":"Manning","year":"2011","journal-title":"J. Orthop. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1177\/0363546508316282","article-title":"Enhancement of tendon-bone osteointegration of anterior cruciate ligament graft using granulocyte colony-stimulating factor","volume":"36","author":"Sasaki","year":"2008","journal-title":"Am. J. Sports Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1177\/0363546511399378","article-title":"Calcium\u2013phosphate matrix with or without TGF-\u03b23 improves tendon-bone healing after rotator cuff repair","volume":"39","author":"Kovacevic","year":"2011","journal-title":"Am. J. Sports Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.arthro.2006.09.003","article-title":"Effects of low-intensity pulsed ultrasound on tendon-bone healing in an intra-articular sheep knee model","volume":"23","author":"Walsh","year":"2007","journal-title":"Arthroscopy"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"513","DOI":"10.2106\/JBJS.M.00009","article-title":"Augmentation of tendon-to-bone healing","volume":"96","author":"Atesok","year":"2014","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2145","DOI":"10.1002\/jbmr.1957","article-title":"The effect of PTH(1\u201334) on fracture healing during different loading conditions","volume":"28","author":"Ellegaard","year":"2013","journal-title":"J. Bone Miner. Res."},{"key":"ref_27","first-page":"210","article-title":"Tensile type of stress fracture neck of femur: Role of teriparatide in the process of healing in a high risk patient for impaired healing of fracture","volume":"10","author":"Malhotra","year":"2013","journal-title":"Clin. Cases Mineral Bone Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00223-010-9360-5","article-title":"Parathyroid hormone and bone healing","volume":"87","author":"Ellegaard","year":"2010","journal-title":"Calcif. Tissue Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.bone.2012.11.037","article-title":"PTH(1\u201334), but not strontium ranelate counteract loss of trabecular thickness and bone strength in disuse osteopenic rats","volume":"53","author":"Bruel","year":"2013","journal-title":"Bone"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1007\/s00198-012-2258-5","article-title":"Promotion of peri-implant bone healing by systemically administered parathyroid hormone (1\u201334) and zoledronic acid adsorbed onto the implant surface","volume":"24","author":"Li","year":"2013","journal-title":"Osteoporos. Int."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1002\/jbmr.5650070110","article-title":"Effects of continuous and intermittent administration and inhibition of resorption on the anabolic response of bone to parathyroid hormone","volume":"7","author":"Hock","year":"1992","journal-title":"J. Bone Miner. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1056\/NEJM200105103441904","article-title":"Effect of parathyroid hormone (1\u201334) on fractures and bone mineral density in postmenopausal women with osteoporosis","volume":"344","author":"Neer","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1359\/jbmr.1999.14.4.536","article-title":"Anabolic effects of human biosynthetic parathyroid hormone fragment (1\u201334), LY333334, on remodeling and mechanical properties of cortical bone in rabbits","volume":"14","author":"Hirano","year":"1999","journal-title":"J. Bone Miner. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.stem.2010.09.012","article-title":"Inhibition of Sca-1-positive skeletal stem cell recruitment by alendronate blunts the anabolic effects of parathyroid hormone on bone remodeling","volume":"7","author":"Wu","year":"2010","journal-title":"Cell Stem Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1007\/s00198-009-0882-5","article-title":"Effects of PTH treatment on tibial bone of ovariectomized rats assessed by in vivo micro-CT","volume":"20","author":"Brouwers","year":"2009","journal-title":"Osteoporos. Int."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1016\/j.joca.2011.07.003","article-title":"Improving subchondral bone integrity reduces progression of cartilage damage in experimental osteoarthritis preceded by osteoporosis","volume":"19","author":"Bellido","year":"2011","journal-title":"Osteoarthr. Cartil."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3324","DOI":"10.1016\/j.biomaterials.2008.04.012","article-title":"In vivo study of anterior cruciate ligament regeneration using mesenchymal stem cells and silk scaffold","volume":"29","author":"Fan","year":"2008","journal-title":"Biomaterials"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/S0749-8063(97)90194-8","article-title":"Integration of hamstring tendon graft with bone in reconstruction of the anterior cruciate ligament","volume":"13","author":"Pinczewski","year":"1997","journal-title":"Arthroscopy"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1089\/ten.tea.2012.0325","article-title":"Local administration of low-dose simvastatin-conjugated gelatin hydrogel for tendon-bone healing in anterior cruciate ligament reconstruction","volume":"19","author":"Oka","year":"2013","journal-title":"Tissue Eng. A"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1892","DOI":"10.1177\/0363546505277140","article-title":"The fate of host and graft cells in early healing of bone tunnel after tendon graft","volume":"33","author":"Kobayashi","year":"2005","journal-title":"Am. J. Sports Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1016\/j.orthres.2005.01.014.1100230627","article-title":"Macrophages accumulate in the early phase of tendon-bone healing","volume":"23","author":"Kawamura","year":"2005","journal-title":"J. Orthop. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/S0749-8063(04)00653-X","article-title":"Enhancement of tendon graft osteointegration using mesenchymal stem cells in a rabbit model of anterior cruciate ligament reconstruction","volume":"20","author":"Lim","year":"2004","journal-title":"Arthroscopy"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1177\/0363546507300057","article-title":"An analysis of soft tissue allograft anterior cruciate ligament reconstruction in a rabbit model: A short-term study of the use of mesenchymal stem cells to enhance tendon osteointegration","volume":"35","author":"Soon","year":"2007","journal-title":"Am. J. Sports Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1038\/nature09262","article-title":"Mesenchymal and haematopoietic stem cells form a unique bone marrow niche","volume":"466","author":"Michurina","year":"2010","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1002\/jbmr.5650101213","article-title":"PTH\/PTHrP receptor expression on osteoblasts and osteocytes but not resorbing bone surfaces in growing rats","volume":"10","author":"Fermor","year":"1995","journal-title":"J. Bone Miner. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.bone.2012.09.016","article-title":"Effects of PTH on osteocyte function","volume":"54","author":"Bellido","year":"2013","journal-title":"Bone"},{"key":"ref_47","first-page":"258409","article-title":"Effects of parathyroid hormone on calcium ions in rat bone marrow mesenchymal stem cells","volume":"2014","author":"Chen","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/jbmr.5650050314","article-title":"Parathyroid hormone stimulates formation of inositol phosphates in a membrane preparation of canine renal cortical tubular cells","volume":"5","author":"Coleman","year":"1990","journal-title":"J. Bone Miner. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1359\/jbmr.070517","article-title":"IGF-I receptor is required for the anabolic actions of parathyroid hormone on bone","volume":"22","author":"Wang","year":"2007","journal-title":"J. Bone Miner. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2365","DOI":"10.1177\/0363546512457648","article-title":"Effects of demineralized bone matrix on tendon-bone healing in an intra-articular rodent model","volume":"40","author":"Lovric","year":"2012","journal-title":"Am. J. Sports Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1002\/jbmr.141","article-title":"Guidelines for assessment of bone microstructure in rodents using micro-computed tomography","volume":"25","author":"Bouxsein","year":"2010","journal-title":"J. Bone Miner. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/15\/10\/17366\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:16:25Z","timestamp":1760217385000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/15\/10\/17366"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,9,29]]},"references-count":51,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2014,10]]}},"alternative-id":["ijms151017366"],"URL":"https:\/\/doi.org\/10.3390\/ijms151017366","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,9,29]]}}}