{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T12:46:45Z","timestamp":1791809205139,"version":"4.3.4"},"reference-count":44,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2026,10,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Diabetic peripheral neuropathy (DPN) is a common and disabling complication of diabetes and a major cause of sensory dysfunction. In established disease, nerve injury may continue despite partial metabolic improvement, suggesting that local nerve microenvironmental mechanisms sustain damage. The mediators linking macrophage activation to Schwann\u2010cell dysfunction and sensory abnormalities remain unclear. We studied matrix metalloproteinase\u201012 (MMP12) in 20\u2010week\u2010old male C57BLKS\/J db\/db mice and normoglycemic m\/m controls. Sciatic nerves were assessed by histology, Luxol fast blue staining, and transmission electron microscopy. Functional studies included motor and sensory nerve conduction, von Frey testing, and Hargreaves testing. RNA sequencing, tissue validation, primary macrophages cultured under high\u2010glucose or mannitol osmotic\u2010control conditions, macrophage\u2010conditioned medium, and the MMP12 inhibitor MMP408 were used to define mechanism and intervention effects. Recombinant fibronectin 1 (FN1), recombinant MMP12, and the TLR4 inhibitor TAK\u2010242 were used to assess the involvement of TLR4 signaling in Schwann cells. Db\/db mice showed demyelination, impaired nerve conduction, and abnormal sensory responses. RNA sequencing highlighted extracellular matrix and cell\u2010adhesion pathways and identified Mmp12 as a hub gene. Diabetic sciatic nerves showed increased MMP12, reduced FN1, and substantial MMP12 colocalization with F4\/80\u2010positive macrophages. Compared with the mannitol osmotic\u2010control condition, high glucose increased macrophage MMP12 expression, while conditioned medium from these cells activated TLR4\/NF\u2010\u03baB signaling, increased c\u2010Jun expression and apoptosis, and impaired Schwann\u2010cell migration. MMP408 partly reversed these changes in\u00a0vitro. Recombinant FN1 and MMP12 cotreatment activated TLR4\/NF\u2010\u03baB\/c\u2010Jun signaling in Schwann cells, and these changes were attenuated by TAK\u2010242. In\u00a0vivo, MMP408 preserved FN1 expression and improved myelin structure, myelin\u2010related protein expression, nerve conduction, and sensory abnormalities. MMP408 reduced serum total cholesterol and triglyceride levels but had no significant effects on body weight, blood glucose, or serum insulin levels. A macrophage\u2010associated MMP12\u2013Fn1 axis may contribute to establish DPN through Schwann\u2010cell dysfunction and represents a potential therapeutic target for diabetic neuropathic sensory dysfunction.<\/jats:p>","DOI":"10.1096\/fj.202601940r","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T14:43:52Z","timestamp":1791470632000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Macrophage\u2010Associated\n                    <scp>MMP12<\/scp>\n                    Disrupts Extracellular Matrix Homeostasis and Promotes Schwann\u2010Cell Dysfunction in Diabetic Peripheral Neuropathy"],"prefix":"10.1096","volume":"40","author":[{"given":"Li","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Neurology, the Affiliated Nanhua Hospital, Hengyang Medical School University of South China  Hengyang Hunan China"},{"name":"Department of Neurosurgery Renmin 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