{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T20:46:12Z","timestamp":1782938772970,"version":"3.54.5"},"reference-count":74,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371008"],"award-info":[{"award-number":["82371008"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81771126"],"award-info":[{"award-number":["81771126"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The aging bone marrow microenvironment is characterized by chronic low\u2010grade inflammation (\u201cinflammaging\u201d), which disrupts skeletal homeostasis and impairs bone regeneration. However, the stromal\u2013immune crosstalk mechanisms sustaining this pathological state remain poorly defined. Here, transcriptomic analysis identified thrombospondin\u20101 (Thbs1) as a key upregulated component of the senescence\u2010associated secretory phenotype (SASP) in aged bone mesenchymal stromal cells (BMSCs). We demonstrate that BMSC\u2010derived Thbs1 drives pro\u2010inflammatory M1 macrophage polarization by suppressing PINK1\/Parkin\u2010mediated mitophagy. Mechanistically, Thbs1 binds to the TGF\u2010\u03b2 type II receptor (Tgfbr2) on macrophages to activate Smad3 signaling, which transcriptionally represses the mitophagy regulator\n                    <jats:italic>Pink1<\/jats:italic>\n                    . This repression leads to mitochondrial superoxide accumulation and redox imbalance, thereby skewing macrophages toward an M1\u2010like phenotype. These Thbs1\u2010activated M1 macrophages, in turn, secrete IL\u20106, which activates the JAK\/STAT3 pathway in BMSCs to inhibit osteogenic differentiation. Crucially, activated Stat3 directly binds the\n                    <jats:italic>Thbs1<\/jats:italic>\n                    promoter, establishing a self\u2010amplifying loop that perpetuates inflammaging and osteogenic decline. In\u00a0vivo, AAV9\u2010mediated Thbs1 knockdown in aged rat bone defects restored mitochondrial homeostasis, promoted an M2 macrophage transition, and significantly enhanced bone repair. Our study reveals a vicious cycle involving the Thbs1\/TGF\u2010\u03b2\/Smad3\/PINK1\u2013IL\u20106\/JAK\/STAT3 axis that sustains inflammaging and osteogenic decline, highlighting Thbs1 as a promising therapeutic target for age\u2010related bone regeneration.\n                  <\/jats:p>","DOI":"10.1111\/acel.70575","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T12:54:55Z","timestamp":1780923295000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Senescent\n                    <scp>BMSC<\/scp>\n                    \u2010Derived Thbs1 Drives Inflammaging and Impairs Bone Regeneration by Suppressing\n                    <scp>PINK1<\/scp>\n                    \/Parkin\u2010Mediated Mitophagy in Macrophages"],"prefix":"10.1111","volume":"25","author":[{"given":"Yifeng","family":"Xing","sequence":"first","affiliation":[{"name":"Clinical Research Center for Oral Tissue Deficiency Diseases of Fujian Province, Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology Fujian Medical University  Fuzhou China"},{"name":"Stomatological Key Laboratory of Fujian College and University and Research Center of Dental and Craniofacial Implants, School and Hospital of Stomatology Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1360-3735","authenticated-orcid":false,"given":"Jingjing","family":"Su","sequence":"additional","affiliation":[{"name":"Stomatological Hospital of Xiamen Medical College  Xiamen China"},{"name":"Xiamen Key Laboratory of Stomatological Disease Diagnosis and Treatment  Xiamen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjun","family":"Lin","sequence":"additional","affiliation":[{"name":"Clinical Research Center for Oral Tissue Deficiency Diseases of Fujian Province, Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nengwen","family":"Huang","sequence":"additional","affiliation":[{"name":"Clinical Research Center for Oral Tissue Deficiency Diseases of Fujian Province, Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology Fujian Medical University  Fuzhou China"},{"name":"Stomatological Key Laboratory of Fujian College and University and Research Center of Dental and Craniofacial Implants, School and Hospital of Stomatology Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sihui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Clinical Research Center for Oral Tissue Deficiency Diseases of Fujian Province, Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology Fujian Medical University  Fuzhou 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Hospital of Stomatology Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Stomatology, Henan Provincial People's Hospital People's Hospital of Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geyuan","family":"Zheng","sequence":"additional","affiliation":[{"name":"Clinical Research Center for Oral Tissue Deficiency Diseases of Fujian Province, Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology Fujian Medical University  Fuzhou China"},{"name":"Stomatological Key Laboratory of Fujian College and University and Research Center of Dental and Craniofacial Implants, School and Hospital of Stomatology Fujian Medical University  Fuzhou 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