{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:10:00Z","timestamp":1785409800824,"version":"3.56.0"},"reference-count":44,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82370958"],"award-info":[{"award-number":["82370958"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81870770"],"award-info":[{"award-number":["81870770"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82370958"],"award-info":[{"award-number":["82370958"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["81870770"],"award-info":[{"award-number":["81870770"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"crossref","award":["2024M763824"],"award-info":[{"award-number":["2024M763824"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"crossref"}]},{"award":["2024M763824"],"award-info":[{"award-number":["2024M763824"]}],"id":[{"id":"https:\/\/ror.org\/0426zh255","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Nickel (Ni) is a ubiquitous trace metal, yet its physiological dynamics and dose-dependent roles in skeletal biology remain unclear. Here we combined elemental mapping, cellular assays, multi-omics and mouse models to define how Ni availability modulates osteogenesis. Ni, together with Manganese (Mn), chromium (Cr) and copper (Cu), was readily detectable in serum from both mice and humans. In situ LA\u2013ICP\u2013MS further showed that Ni levels in embryonic calvaria rose significantly across stages and CaO exhibited a consistent upward trend, suggesting coordinated accumulation of Ni with cranial mineralization. In vitro, Ni exerted biphasic effects on bone marrow mesenchymal stromal cells (BMSCs): high-dose Ni (100 \u03bcM) suppressed proliferation, elevated ROS, and induced time-dependent upregulation of Hmox1 and Nos2, consistent with escalating oxidative\/nitrosative stress. By contrast, low-dose Ni (0.1 \u03bcM) enhanced matrix mineralization, whereas this pro-mineralization effect was attenuated at higher concentrations. In vivo, both Ni deprivation and Ni overload impaired bone formation: a Ni-free diet caused trabecular rarefaction and reduced mineral apposition, while high Ni hindered bone development of mice, especially in the early-stage intake. Mechanistically, RNA-seq and Ni-NTA proteomics identified Ni-driven osteogenic transcriptional remodeling and increased Ni-binding proteins, prioritizing integrin-linked kinase (ILK) as a Ni-inducible binder. ILK was required for osteogenic differentiation, and low-dose Ni activated AKT\u2013mTOR signaling in an ILK-dependent manner. Finally, low-dose Ni-pretreated collagen scaffolds enhanced calvarial defect repair. Together, these findings define a narrow physiological window in which Ni supports osteogenesis via ILK\u2013AKT\u2013mTOR, whereas both deficiency and excess disrupt skeletal accrual.<\/jats:p>","DOI":"10.3390\/ijms27104538","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T07:35:43Z","timestamp":1779176143000},"page":"4538","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dose-Dependent Effects of Nickel on Skeletal Development: Physiological Necessity and the Threshold of Toxicity"],"prefix":"10.3390","volume":"27","author":[{"given":"Xiaoxin","family":"Ma","sequence":"first","affiliation":[{"name":"Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Huang","sequence":"additional","affiliation":[{"name":"Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2069-3660","authenticated-orcid":false,"given":"Jinyu","family":"Li","sequence":"additional","affiliation":[{"name":"Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixian","family":"Wu","sequence":"additional","affiliation":[{"name":"Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runxin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daqi","family":"Huang","sequence":"additional","affiliation":[{"name":"Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Gao","sequence":"additional","affiliation":[{"name":"Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1359-0252","authenticated-orcid":false,"given":"Chuanjiang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"20170218","DOI":"10.1098\/rstb.2017.0218","article-title":"From Skeletal Development to the Creation of Pluripotent Stem Cell-Derived Bone-Forming Progenitors","volume":"373","author":"Tam","year":"2018","journal-title":"Philos. 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