{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:15:30Z","timestamp":1788909330539,"version":"build-2803163510"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T00:00:00Z","timestamp":1734652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"publisher","award":["2018YFA0800800"],"award-info":[{"award-number":["2018YFA0800800"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81730066"],"award-info":[{"award-number":["81730066"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Background: Premature osteoporosis caused by parathyroid hormone-related peptide (PTHrP) dysfunction presents significant bone health challenges. The role of p16-mediated cellular senescence in this condition remains unclear. Methods: Using a Pthrp knock-in (KI) mouse model lacking the nuclear localization sequence and C-terminus of PTHrP, we generated p16\u207b\u2044\u207bKI mice and compared them with wild-type, p16\u207b\u2044\u207b, and KI mice. We analyzed survival, skeletal phenotypes, bone marrow mesenchymal stem cell (BM-MSC) function, and molecular markers of senescence. Results: Genetic ablation of p16 in KI mice extended their lifespan, increased body size and weight, and improved skeletal growth. Micro-CT analysis revealed significantly increased bone volume, while histological studies showed enhanced chondrocyte proliferation and osteoblast function in p16\u207b\u2044\u207bKI mice compared to KI mice. In vitro experiments demonstrated enhanced differentiation capacity and reduced senescence of BM-MSCs from p16\u207b\u2044\u207bKI mice, as evidenced by increased colony formation and osteogenic marker expression. Molecular analyses indicated that p16 knockout partially reversed oxidative stress, DNA damage, and cellular senescence observed in KI mice, shown by upregulated antioxidant enzymes, reduced DNA damage markers, and decreased senescence markers. Conclusions: p16-mediated cellular senescence plays a crucial role in premature osteoporosis caused by PTHrP dysfunction. Targeting cellular senescence pathways may offer a promising therapeutic strategy for treating premature osteoporosis and age-related bone loss.<\/jats:p>","DOI":"10.1093\/stmcls\/sxae088","type":"journal-article","created":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T11:11:01Z","timestamp":1734693061000},"source":"Crossref","is-referenced-by-count":3,"title":["Genetic ablation of p16 mitigates premature osteoporosis induced by PTHrP nuclear localization sequence and C-terminal deletion through inhibition of cellular senescence"],"prefix":"10.1093","volume":"43","author":[{"given":"Yongli","family":"Han","sequence":"first","affiliation":[{"name":"Department of Nursing, Changzhou Hygiene Vocational Technology College , Changzhou 213000 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanxin","family":"Qiao","sequence":"additional","affiliation":[{"name":"The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University , Nanjing 211166 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Xue","sequence":"additional","affiliation":[{"name":"The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University , Nanjing 211166 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2682-3502","authenticated-orcid":false,"given":"Dengshun","family":"Miao","sequence":"additional","affiliation":[{"name":"The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University , Nanjing 211166 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhan","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Children\u2019s Hospital of Nanjing Medical University , Nanjing 210008 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,12,20]]},"reference":[{"key":"2025042307471200400_CIT0001","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1016\/S0140-6736(18)32112-3","article-title":"Osteoporosis","volume":"393","author":"Compston","year":"2019","journal-title":"Lancet"},{"key":"2025042307471200400_CIT0002","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1210\/er.2009-0044","article-title":"Genetics of osteoporosis","volume":"31","author":"Ralston","year":"2010","journal-title":"Endocr Rev"},{"key":"2025042307471200400_CIT0003","doi-asserted-by":"publisher","first-page":"2947","DOI":"10.1210\/jc.2012-2142","article-title":"Parathyroid hormone-related protein: an update","volume":"97","author":"Wysolmerski","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"2025042307471200400_CIT0004","doi-asserted-by":"publisher","first-page":"1024","DOI":"10.1126\/science.1658941","article-title":"A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide","volume":"254","author":"Juppner","year":"1991","journal-title":"Science"},{"key":"2025042307471200400_CIT0005","doi-asserted-by":"publisher","first-page":"2402","DOI":"10.1172\/JCI24918","article-title":"Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34","volume":"115","author":"Miao","year":"2005","journal-title":"J Clin Invest"},{"key":"2025042307471200400_CIT0006","doi-asserted-by":"publisher","first-page":"1173","DOI":"10.1172\/JCI14817","article-title":"Parathyroid hormone is essential for normal fetal bone formation","volume":"109","author":"Miao","year":"2002","journal-title":"J Clin Invest"},{"key":"2025042307471200400_CIT0007","doi-asserted-by":"publisher","first-page":"20309","DOI":"10.1073\/pnas.0805690105","article-title":"Severe growth retardation and early lethality in mice lacking the nuclear localization sequence and C-terminus of PTH-related protein","volume":"105","author":"Miao","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2025042307471200400_CIT0008","doi-asserted-by":"publisher","first-page":"508","DOI":"10.7150\/ijbs.23318","article-title":"DNA damage checkpoint pathway modulates the regulation of skeletal growth and osteoblastic bone formation by parathyroid hormone-related peptide","volume":"14","author":"Zhang","year":"2018","journal-title":"Int J Biol Sci"},{"key":"2025042307471200400_CIT0009","doi-asserted-by":"publisher","first-page":"1969","DOI":"10.1002\/jbmr.2544","article-title":"The p27 pathway modulates the regulation of skeletal growth and osteoblastic bone formation by parathyroid hormone-related peptide [in Eng]","volume":"30","author":"Zhu","year":"2015","journal-title":"J Bone Miner Res"},{"key":"2025042307471200400_CIT0010","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1038\/nm.4385","article-title":"Targeting cellular senescence prevents age-related bone loss in mice","volume":"23","author":"Farr","year":"2017","journal-title":"Nat Med"},{"key":"2025042307471200400_CIT0011","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1038\/nature13193","article-title":"The role of senescent cells in ageing","volume":"509","author":"van Deursen","year":"2014","journal-title":"Nature"},{"key":"2025042307471200400_CIT0012","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1007\/s11914-019-00504-2","article-title":"Targeting cell senescence for the treatment of age-related bone loss","volume":"17","author":"Pignolo","year":"2019","journal-title":"Curr Osteoporos Rep"},{"key":"2025042307471200400_CIT0013","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1093\/carcin\/bgq052","article-title":"Role of the RNA-binding protein HuR in human renal cell carcinoma","volume":"31","author":"Danilin","year":"2010","journal-title":"Carcinogenesis"},{"key":"2025042307471200400_CIT0014","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1177\/0192623314547279","article-title":"Postnatal development of the testis in the rat: morphologic study and correlation of morphology to neuroendocrine parameters","volume":"43","author":"Picut","year":"2015","journal-title":"Toxicol Pathol"},{"key":"2025042307471200400_CIT0015","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.1359\/jbmr.070507","article-title":"Age-related changes in trabecular architecture differ in female and male C57BL\/6J mice","volume":"22","author":"Glatt","year":"2007","journal-title":"J Bone Miner Res"},{"key":"2025042307471200400_CIT0016","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1007\/s00223-003-0101-x","article-title":"Growth of C57BL\/6 mice and the material and mechanical properties of cortical bone from the tibia","volume":"74","author":"Somerville","year":"2004","journal-title":"Calcif Tissue Int"},{"key":"2025042307471200400_CIT0017","doi-asserted-by":"publisher","first-page":"1766","DOI":"10.1359\/JBMR.050608","article-title":"Exogenous PTH-related protein and PTH improve mineral and skeletal status in 25-hydroxyvitamin D-1alpha-hydroxylase and PTH double knockout mice [in eng]","volume":"20","author":"Xue","year":"2005","journal-title":"J Bone Miner Res"},{"key":"2025042307471200400_CIT0018","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.1002\/jbmr.3117","article-title":"Targeting Notch-Activated M1 macrophages attenuates joint tissue damage in a mouse model of inflammatory arthritis","volume":"32","author":"Sun","year":"2017","journal-title":"J Bone Miner Res"},{"key":"2025042307471200400_CIT0019","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1177\/002215540205000305","article-title":"Histochemical localization of alkaline phosphatase activity in decalcified bone and cartilage","volume":"50","author":"Miao","year":"2002","journal-title":"J Histochem Cytochem"},{"key":"2025042307471200400_CIT0020","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1210\/endo.142.2.7976","article-title":"Osteomalacia in hyp mice is associated with abnormal phex expression and with altered bone matrix protein expression and deposition","volume":"142","author":"Miao","year":"2001","journal-title":"Endocrinology"},{"key":"2025042307471200400_CIT0021","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1016\/j.freeradbiomed.2021.12.010","article-title":"Inhibition of Nrf2 degradation alleviates age-related osteoporosis induced by 1,25-Dihydroxyvitamin D deficiency","volume":"178","author":"Yang","year":"2022","journal-title":"Free Radic Biol Med"},{"key":"2025042307471200400_CIT0022","doi-asserted-by":"publisher","first-page":"2097","DOI":"10.1016\/j.gendis.2022.12.016","article-title":"DLX5 promotes Col10a1 expression and chondrocyte hypertrophy and is involved in osteoarthritis progression","volume":"10","author":"Chen","year":"2023","journal-title":"Genes Dis"},{"key":"2025042307471200400_CIT0023","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1172\/jci22475","article-title":"Ink4a\/Arf expression is a biomarker of aging","volume":"114","author":"Krishnamurthy","year":"2004","journal-title":"J Clin Invest"},{"key":"2025042307471200400_CIT0024","doi-asserted-by":"publisher","first-page":"1332","DOI":"10.3390\/life12091332","article-title":"P16INK4A-More than a senescence marker","volume":"12","author":"Safwan-Zaiter","year":"2022","journal-title":"Life (Basel)"},{"key":"2025042307471200400_CIT0025","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1038\/nrc3960","article-title":"Forging a signature of in vivo senescence","volume":"15","author":"Sharpless","year":"2015","journal-title":"Nat Rev Cancer"},{"key":"2025042307471200400_CIT0026","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1038\/366704a0","article-title":"A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D\/CDK4","volume":"366","author":"Serrano","year":"1993","journal-title":"Nature"},{"key":"2025042307471200400_CIT0027","doi-asserted-by":"publisher","first-page":"7035","DOI":"10.1038\/ncomms8035","article-title":"Ablation of the p16(INK4a) tumour suppressor reverses ageing phenotypes of klotho mice","volume":"6","author":"Sato","year":"2015","journal-title":"Nat Commun"},{"key":"2025042307471200400_CIT0028","doi-asserted-by":"publisher","first-page":"e13095","DOI":"10.1111\/acel.13095","article-title":"1,25-Dihydroxyvitamin D protects against age-related osteoporosis by a novel VDR-Ezh2-p16 signal axis","volume":"19","author":"Yang","year":"2020","journal-title":"Aging Cell"},{"issue":"3","key":"2025042307471200400_CIT0029","doi-asserted-by":"publisher","first-page":"e154888","DOI":"10.1172\/JCI154888","article-title":"Cellular senescence and the skeleton: pathophysiology and therapeutic implications","volume":"132","author":"Khosla","year":"2022","journal-title":"J Clin Invest"},{"key":"2025042307471200400_CIT0030","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1038\/nature16932","article-title":"Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan","volume":"530","author":"Baker","year":"2016","journal-title":"Nature"},{"key":"2025042307471200400_CIT0031","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.1016\/j.cell.2017.05.015","article-title":"Senescence in health and disease","volume":"169","author":"He","year":"2017","journal-title":"Cell"},{"key":"2025042307471200400_CIT0032","doi-asserted-by":"publisher","first-page":"775","DOI":"10.3892\/ijmm.2017.2912","article-title":"Senescence of mesenchymal stem cells (Review)","volume":"39","author":"Li","year":"2017","journal-title":"Int J Mol Med"},{"key":"2025042307471200400_CIT0033","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1038\/nm.4010","article-title":"Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice","volume":"22","author":"Chang","year":"2016","journal-title":"Nat Med"},{"key":"2025042307471200400_CIT0034","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1146\/annurev-pathol-121808-102144","article-title":"The senescence-associated secretory phenotype: the dark side of tumor suppression","volume":"5","author":"Coppe","year":"2010","journal-title":"Annu Rev Pathol"},{"key":"2025042307471200400_CIT0035","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1038\/s41586-022-05535-x","article-title":"Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration","volume":"613","author":"Moiseeva","year":"2023","journal-title":"Nature"},{"key":"2025042307471200400_CIT0036","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1159\/000382054","article-title":"Cellular senescence and the biology of aging, disease, and frailty","volume":"83","author":"LeBrasseur","year":"2015","journal-title":"Nestle Nutr Inst Workshop Ser"},{"key":"2025042307471200400_CIT0037","doi-asserted-by":"publisher","first-page":"e12997","DOI":"10.7554\/eLife.12997","article-title":"Targeting senescent cells enhances adipogenesis and metabolic function in old age","volume":"4","author":"Xu","year":"2015","journal-title":"Elife"},{"key":"2025042307471200400_CIT0038","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/nature12984","article-title":"The bone marrow niche for haematopoietic stem cells","volume":"505","author":"Morrison","year":"2014","journal-title":"Nature"},{"key":"2025042307471200400_CIT0039","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1002\/jbmr.1834","article-title":"beta-catenin promotes bone formation and suppresses bone resorption in postnatal growing mice","volume":"28","author":"Chen","year":"2013","journal-title":"J Bone Miner Res"},{"key":"2025042307471200400_CIT0040","doi-asserted-by":"publisher","first-page":"e71318","DOI":"10.1371\/journal.pone.0071318","article-title":"Osterix-cre labeled progenitor cells contribute to the formation and maintenance of the bone marrow stroma","volume":"8","author":"Liu","year":"2013","journal-title":"PLoS One"}],"container-title":["Stem Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/stmcls\/advance-article-pdf\/doi\/10.1093\/stmcls\/sxae088\/61244229\/sxae088.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/43\/4\/sxae088\/61244229\/sxae088.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/43\/4\/sxae088\/61244229\/sxae088.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T11:47:26Z","timestamp":1745408846000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/stmcls\/article\/doi\/10.1093\/stmcls\/sxae088\/7929429"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,20]]},"references-count":40,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,4,22]]}},"URL":"https:\/\/doi.org\/10.1093\/stmcls\/sxae088","relation":{},"ISSN":["1066-5099","1549-4918"],"issn-type":[{"value":"1066-5099","type":"print"},{"value":"1549-4918","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,4]]},"published":{"date-parts":[[2024,12,20]]},"article-number":"sxae088"}}