{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T18:18:40Z","timestamp":1793125120059,"version":"4.5.0"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T00:00:00Z","timestamp":1751414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The role of the sympathetic nervous system in bone metabolism remains unclear. Given that <jats:sup>99m<\/jats:sup>Tc-methylene diphosphonate ([<jats:sup>99m<\/jats:sup>Tc]Tc-MDP) uptake reflects active bone formation and mineralization, this study aims to investigate the effects of sympathetic denervation on bone formation in rats using [<jats:sup>99m<\/jats:sup>Tc]Tc-MDP SPECT\/CT imaging.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>Twenty rats were randomly assigned to a superior cervical ganglionectomy (SCGx) group (n = 10) or a sham-operated control group (n = 10). Circular cranial fractures were surgically created in both groups. Micro SPECT\/CT imaging was performed at 3, 6, and 9 weeks postoperatively to assess bone mineral density (BMD), bone volume\/tissue volume (BV\/TV), and bone volume (BV). In a separate experiment, 12 additional rats underwent either bilateral lumbar sympathectomy (n = 6) or sham operation (n = 6). At 9 weeks, [<jats:sup>99m<\/jats:sup>Tc]Tc-MDP biodistribution in harvested bone tissues was measured. Immunohistochemical staining for tyrosine hydroxylase (TH) and Ki67 was used to evaluate sympathetic innervation and cell proliferation in craniums, while immunofluorescence co-labeling for Ki67 and osteopontin (OPN) identified proliferating osteoblasts. <jats:italic>In vitro<\/jats:italic>, MC3T3-E1 osteoblasts were treated with norepinephrine (NE) or control medium for 24 hours. Cell proliferation was assessed using EdU staining. Additionally, sympathetic neurons isolated from neonatal rats were co-cultured with MC3T3-E1 cells in Transwell systems, and mineralization and alkaline phosphatase (ALP) activity were evaluated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Successful SCGx was confirmed by signs of Horner\u2019s syndrome. SCGx rats exhibited significantly higher [<jats:sup>99m<\/jats:sup>Tc]Tc-MDP uptake and increased BMD, BV\/TV, and BV in peri-fracture regions at all time points (<jats:italic>p<\/jats:italic> &amp;lt; 0.0001). Lumbar sympathectomy increased tracer uptake in femurs, tibias, lumbar vertebrae, and sacra (<jats:italic>p<\/jats:italic> &amp;lt; 0.01), but not in cervical or thoracic vertebrae. TH expression decreased, while Ki67 and OPN levels increased in SCGx craniums. NE suppressed MC3T3-E1 proliferation (<jats:italic>p<\/jats:italic> &amp;lt; 0.0001), and co-culture with sympathetic neurons reduced mineralization and ALP activity (both <jats:italic>p<\/jats:italic> &amp;lt; 0.0001).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Sympathectomy can enhance osteoblast prolifeation and augment bone formation, which can be effectively assessed and quantified using [<jats:sup>99m<\/jats:sup>Tc]Tc-MDP SPECT\/CT imaging.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2025.1580230","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T09:45:34Z","timestamp":1751449534000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Augmentation of bone formation by sympathectomy in rats as evaluated by [99mTc]Tc-MDP"],"prefix":"10.3389","volume":"16","author":[{"given":"Zili","family":"Cai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuting","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuehong","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weibing","family":"Miao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03398","article-title":"Leptin regulation of bone resorption by the sympathetic nervous system and CART","volume":"434","author":"Elefteriou","year":"2005","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)01049-8","article-title":"Leptin regulates bone formation via the sympathetic nervous system","volume":"111","author":"Takeda","year":"2002","journal-title":"Cell"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/med.22031","article-title":"Emerging roles of nerve-bone axis in modulating skeletal system","volume":"44","author":"Li","year":"2024","journal-title":"Medicinal Res Rev"},{"key":"B4","doi-asserted-by":"publisher","first-page":"035018","DOI":"10.1088\/1748-6041\/11\/3\/035018","article-title":"A bioceramic with enhanced osteogenic properties to regulate the function of osteoblastic and osteocalastic cells for bone tissue regeneration","volume":"11","author":"Roohani-Esfahani","year":"2016","journal-title":"Biomed Materials"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1039\/c1mb05242j","article-title":"Bisphosphonates as radionuclide carriers for imaging or systemic therapy","volume":"7","author":"Palma","year":"2011","journal-title":"Mol Biosyst"},{"key":"B6","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.lfs.2018.05.030","article-title":"18F-Fluoride PET\/CT and 99mTc-MDP SPECT\/CT can detect bone cancer at early stage in rodents","volume":"206","author":"Alves","year":"2018","journal-title":"Life Sci"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2005.04.027","article-title":"Binding studies of [18F]-fluoride and polyphosphonates radiolabelled with [99mTc],[111In],[153Sm] and [188Re] on bone compartments: verification of the pre vivo model","volume":"37","author":"Mitterhauser","year":"2005","journal-title":"Bone"},{"key":"B8","article-title":"99mTc-MDP uptake and histological changes during rat bone marrow regeneration","volume":"15","author":"Chisin","year":"1988","journal-title":"Int J Radiat Appl Instrumentation. 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