{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T13:35:37Z","timestamp":1777469737611,"version":"3.51.4"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T00:00:00Z","timestamp":1754352000000},"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. Bioeng. Biotechnol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Diabetes mellitus (DM) is a chronic metabolic disease, which can not only induce osteoporosis but also accelerate intervertebral disc degeneration (IVDD). Ipriflavone (IP), as a derivative of isoflavones, can not only control the level of blood glucose, but also improve the regulation of osteoporosis and cartilage extracellular matrix metabolism. However, there is no study on whether IP can effectively improve DM with IVDD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Sixty healthy female C57BL\/6J mice were randomly assigned into five groups (Sham, Instability of lumbar spine (ILS), streptozotocin (STZ), ILS + STZ and ILS + STZ + IP groups; 12 per group). The body weight, fasting glucose and blood insulin levels were evaluated in each group of mice. The pathology of DM with IVDD was assessed by Micro-CT (\u03bcCT), Van Gieson (VG) staining, Alcian blue (Ab) staining, immunohistochemistry, Western blot and real-time polymerase chain reaction (RT-PCR).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>IP significantly lowed fasting blood glucose and blood insulin levels. Histomorphological analysis revealed that IVDD was significantly exacerbated by the coexistence of ILS and DM, and markedly alleviated by IP. In details, IP markedly improved osteoporosis and microarchitecture of EP and vertebrae. Furthermore, IP ameliorated the cartilage extracellular matrix degradation, significantly increased Aggrecan and Col II expression and decreased the expression of MMP13 and ADAMTS-4. Moreover, IP inhibited EP sclerosis and NP pyroptosis by decreasing Runx2, Osterix, NLRP3, ASC, N-GSDMD and caspase1 expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The coexistence of ILS and DM further aggravates abnormal metabolic pathology and IVDD, which could be retarded by IP, suggesting that IP may be a potential therapeutic target for amelioration of the progression of DM with IVDD.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fbioe.2025.1639117","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T05:24:06Z","timestamp":1754371446000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Ipriflavone ameliorates intervertebral disc degeneration by inhibiting osteoporosis of vertebral body and pyroptosis of the nucleus pulposus in instability of lumbar spine and diabetic mice"],"prefix":"10.3389","volume":"13","author":[{"given":"Qi","family":"Sun","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hai-Jing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gang","family":"Ji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ya-Heng","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gao-Cen","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shao-Shi","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lu-Feng","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Jie","family":"Jin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue-Li","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin-Yu","family":"Nan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang-Cheng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guo-Bin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1177\/039463201002300404","article-title":"Limited joint mobility in diabetes and ageing: recent advances in pathogenesis and therapy","volume":"23","author":"Abate","year":"2010","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"e031592","DOI":"10.1136\/bmjopen-2019-031592","article-title":"Central sensitisation and functioning in patients with chronic low back pain: protocol for a cross-sectional and cohort study","volume":"10","author":"Ansuategui Echeita","year":"2020","journal-title":"BMJ Open"},{"key":"B4","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1186\/s13098-023-01067-0","article-title":"The role of wnt signaling in diabetes-induced osteoporosis","volume":"15","author":"Bao","year":"2023","journal-title":"Diabetol. Metab. Syndr."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1475","DOI":"10.2174\/1389557519666190617150051","article-title":"The roles of flavonols\/flavonoids in neurodegeneration and neuroinflammation","volume":"20","author":"Calis","year":"2020","journal-title":"Mini Rev. Med. Chem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"3033","DOI":"10.2147\/dddt.s170816","article-title":"Sintered dicalcium pyrophosphate treatment attenuates estrogen deficiency-associated disc degeneration in ovariectomized rats","volume":"12","author":"Chen","year":"2018","journal-title":"Drug Des. Devel Ther."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.3904\/kjim.2022.168","article-title":"Musculoskeletal complications in patients with diabetes mellitus","volume":"37","author":"Choi","year":"2022","journal-title":"Korean J. Intern Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2130","DOI":"10.3390\/ijms23042130","article-title":"Modulation of miR-204 expression during chondrogenesis","volume":"23","author":"Dalle","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"3316","DOI":"10.3892\/ijmm.2018.3522","article-title":"Cyclic mechanical tension reinforces DNA damage and activates the p53-p21-Rb pathway to induce premature senescence of nucleus pulposus cells","volume":"41","author":"Feng","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"772","DOI":"10.1038\/s41598-020-80756-6","article-title":"Aberrant spinal mechanical loading stress triggers intervertebral disc degeneration by inducing pyroptosis and nerve ingrowth","volume":"11","author":"Fu","year":"2021","journal-title":"Sci. Rep."},{"key":"B11","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/s41418-017-0012-4","article-title":"Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018","volume":"25","author":"Galluzzi","year":"2018","journal-title":"Cell Death Differ."},{"key":"B12","doi-asserted-by":"publisher","first-page":"4669","DOI":"10.26355\/eurrev_201807_15527","article-title":"Ipriflavone promotes osteogenesis of MSCs derived from osteoporotic rats","volume":"22","author":"Gao","year":"2018","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"5857","DOI":"10.2147\/jir.s382069","article-title":"Pyroptosis and intervertebral disc degeneration: mechanistic insights and therapeutic implications","volume":"15","author":"Ge","year":"2022","journal-title":"J. Inflamm. Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1007\/s10787-022-01098-5","article-title":"Maltol ameliorates intervertebral disc degeneration through inhibiting PI3K\/AKT\/NF-\u03baB pathway and regulating NLRP3 inflammasome-mediated pyroptosis","volume":"31","author":"Gong","year":"2023","journal-title":"Inflammopharmacology"},{"key":"B100","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1186\/s13075-019-1895-x","article-title":"Ipriflavone attenuates the degeneration of cartilage by blocking the Indian hedgehog pathway","volume":"21","author":"Guo","year":"2019","journal-title":"Arthritis Res Ther"},{"key":"B15","doi-asserted-by":"publisher","first-page":"104860","DOI":"10.1016\/j.phrs.2020.104860","article-title":"The efficacy and safety of ipriflavone in postmenopausal women with osteopenia or osteoporosis: a systematic review and meta-analysis","volume":"159","author":"Hu","year":"2020","journal-title":"Pharmacol. Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1633","DOI":"10.1126\/science.abb9818","article-title":"Succination inactivates gasdermin D and blocks pyroptosis","volume":"369","author":"Humphries","year":"2020","journal-title":"Science"},{"key":"B17","doi-asserted-by":"publisher","first-page":"3965","DOI":"10.3390\/ijms22083965","article-title":"Inhibition of autophagy at different stages by ATG5 knockdown and chloroquine supplementation enhances consistent human disc cellular apoptosis and senescence induction rather than extracellular matrix catabolism","volume":"22","author":"Ito","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"dmm036012","DOI":"10.1242\/dmm.036012","article-title":"Dietary advanced glycation end-product consumption leads to mechanical stiffening of murine intervertebral discs","volume":"11","author":"Krishnamoorthy","year":"2018","journal-title":"Dis. Model Mech."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1355503","DOI":"10.3389\/fimmu.2024.1355503","article-title":"From hyperglycemia to intervertebral disc damage: exploring diabetic-induced disc degeneration","volume":"15","author":"Li","year":"2024","journal-title":"Front. Immunol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.14336\/ad.2022.0129","article-title":"The potential role of cytokines in diabetic intervertebral disc degeneration","volume":"13","author":"Li","year":"2022","journal-title":"Aging Dis."},{"key":"B21","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1186\/s13018-018-0755-8","article-title":"The potential effect of type 2 diabetes mellitus on lumbar disc degeneration: a retrospective single-center study","volume":"13","author":"Liu","year":"2018","journal-title":"J. Orthop. Surg. Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1150835","DOI":"10.3389\/fphar.2023.1150835","article-title":"Natural products can modulate inflammation in intervertebral disc degeneration","volume":"14","author":"Liu","year":"2023","journal-title":"Front. Pharmacol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2\u2212\u0394\u0394CT method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1828","DOI":"10.1097\/00007632-199708150-00006","article-title":"Effects of chondroitinase ABC and chymopapain on spinal motion segment biomechanics. An in vivo biomechanical, radiologic, and histologic canine study","volume":"22","author":"Lu","year":"1997","journal-title":"Spine (Phila Pa 1976)"},{"key":"B25","doi-asserted-by":"publisher","first-page":"2208","DOI":"10.3390\/cells9102208","article-title":"The relationship between diabetes mellitus type II and intervertebral disc degeneration in diabetic rodent models: a systematic and comprehensive review","volume":"9","author":"Mahmoud","year":"2020","journal-title":"Cells"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2018\/3839872","article-title":"Musculoskeletal disorders in patients with diabetes mellitus: a cross-sectional study","volume":"2018","author":"Majjad","year":"2018","journal-title":"Int. J. Rheumatol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1097\/01.brs.0000148152.04401.20","article-title":"A novel rabbit model of mild, reproducible disc degeneration by an anulus needle puncture: correlation between the degree of disc injury and radiological and histological appearances of disc degeneration","volume":"30","author":"Masuda","year":"2005","journal-title":"Spine (Phila Pa 1976)"},{"key":"B28","doi-asserted-by":"publisher","first-page":"5014","DOI":"10.3390\/nu15245014","article-title":"Effects of isoflavonoid and vitamin D synergism on bone mineral Density-A systematic and critical review","volume":"15","author":"Miedziaszczyk","year":"2023","journal-title":"Nutrients"},{"key":"B29","doi-asserted-by":"publisher","first-page":"974690","DOI":"10.3389\/fnagi.2022.974690","article-title":"Forsythoside B ameliorates diabetic cognitive dysfunction by inhibiting hippocampal neuroinflammation and reducing synaptic dysfunction in ovariectomized mice","volume":"14","author":"Nan","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e13572","DOI":"10.1111\/acel.13572","article-title":"Ipriflavone as a non-steroidal glucocorticoid receptor antagonist ameliorates diabetic cognitive impairment in mice","volume":"21","author":"Nie","year":"2022","journal-title":"Aging Cell"},{"key":"B31","doi-asserted-by":"publisher","first-page":"E557","DOI":"10.1097\/brs.0000000000002427","article-title":"A mouse intervertebral disc degeneration model by surgically induced instability","volume":"43","author":"Oichi","year":"2018","journal-title":"Spine (Phila Pa 1976)"},{"key":"B32","doi-asserted-by":"publisher","first-page":"S33","DOI":"10.1016\/j.joca.2021.05.055","article-title":"Therapeutic molecules for osteoarthritis treatment. Role of phloretin, ipriflavone and raloxifene in lipopolysaccharide induced osteoarthritic chondrocytes","volume":"29","author":"Paesa","year":"2021","journal-title":"Osteoarthr. Cartil."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.1038\/s41423-021-00670-3","article-title":"An update on the regulatory mechanisms of NLRP3 inflammasome activation","volume":"18","author":"Paik","year":"2021","journal-title":"Cell Mol. Immunol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.ecl.2021.03.006","article-title":"Diabetes and osteoporosis: part II, clinical management","volume":"50","author":"Schacter","year":"2021","journal-title":"Endocrinol. Metab. Clin. North Am."},{"key":"B35","doi-asserted-by":"publisher","first-page":"e12975","DOI":"10.1111\/cpr.12975","article-title":"RNA-Binding protein HuR suppresses senescence through Atg7 mediated autophagy activation in diabetic intervertebral disc degeneration","volume":"54","author":"Shao","year":"2021","journal-title":"Cell Prolif."},{"key":"B36","doi-asserted-by":"publisher","first-page":"e13438","DOI":"10.1111\/cpr.13438","article-title":"Roles of p38 MAPK signalling in intervertebral disc degeneration","volume":"56","author":"Shi","year":"2023","journal-title":"Cell Prolif."},{"key":"B37","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1186\/s13018-021-02504-4","article-title":"Raloxifene retards the progression of adjacent segmental intervertebral disc degeneration by inhibiting apoptosis of nucleus pulposus in ovariectomized rats","volume":"16","author":"Sun","year":"","journal-title":"J. Orthop. Surg. Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1186\/s13075-021-02525-8","article-title":"Denosumab alleviates intervertebral disc degeneration adjacent to lumbar fusion by inhibiting endplate osteochondral remodeling and vertebral osteoporosis in ovariectomized rats","volume":"23","author":"Sun","year":"","journal-title":"Arthritis Res. Ther."},{"key":"B39","doi-asserted-by":"publisher","first-page":"5720","DOI":"10.1111\/jcmm.13848","article-title":"Polydatin suppresses nucleus pulposus cell senescence, promotes matrix homeostasis and attenuates intervertebral disc degeneration in rats","volume":"22","author":"Wang","year":"2018","journal-title":"J. Cell Mol. Med."},{"key":"B40","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1080\/08941939.2021.1953640","article-title":"Intervertebral disc degeneration models for pathophysiology and regenerative therapy -Benefits and limitations","volume":"35","author":"Wang","year":"","journal-title":"J. Invest. Surg."},{"key":"B41","doi-asserted-by":"publisher","first-page":"3570","DOI":"10.1002\/jmv.27813","article-title":"Cell pyroptosis in picornavirus and its potential for treating viral infection","volume":"94","author":"Wang","year":"","journal-title":"J. Med. Virol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1186\/s13075-018-1701-1","article-title":"Osteoporosis of the vertebra and osteochondral remodeling of the endplate causes intervertebral disc degeneration in ovariectomized mice","volume":"20","author":"Xiao","year":"2018","journal-title":"Arthritis Res. Ther."},{"key":"B43","doi-asserted-by":"publisher","first-page":"100978","DOI":"10.1016\/j.arr.2019.100978","article-title":"Intervertebral disc ageing and degeneration: the antiapoptotic effect of oestrogen","volume":"57","author":"Yang","year":"2020","journal-title":"Ageing Res. Rev."},{"key":"B44","doi-asserted-by":"publisher","first-page":"e0237929","DOI":"10.1371\/journal.pone.0237929","article-title":"Ipriflavone and ipriflavone loaded albumin nanoparticles reverse lipopolysaccharide induced neuroinflammation in rats","volume":"15","author":"Yassa","year":"2020","journal-title":"PLoS One"},{"key":"B45","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/s10020-023-00623-8","article-title":"BMP7 ameliorates intervertebral disc degeneration in type 1 diabetic rats by inhibiting pyroptosis of nucleus pulposus cells and NLRP3 inflammasome activity","volume":"29","author":"Yu","year":"2023","journal-title":"Mol. Med."},{"key":"B46","doi-asserted-by":"publisher","first-page":"3665","DOI":"10.1111\/jcmm.14268","article-title":"Apoptotic bodies from endplate chondrocytes enhance the oxidative stress-induced mineralization by regulating PPi metabolism","volume":"23","author":"Yuan","year":"2019","journal-title":"J. Cell Mol. Med."},{"key":"B47","doi-asserted-by":"publisher","first-page":"11742","DOI":"10.1111\/jcmm.15784","article-title":"Mesenchymal stem cells-derived exosomes ameliorate intervertebral disc degeneration through inhibiting pyroptosis","volume":"24","author":"Zhang","year":"","journal-title":"J. Cell Mol. Med."},{"key":"B48","doi-asserted-by":"publisher","first-page":"8950","DOI":"10.1111\/jcmm.15528","article-title":"Bmi deficiency causes oxidative stress and intervertebral disc degeneration which can be alleviated by antioxidant treatment","volume":"24","author":"Zhang","year":"","journal-title":"J. Cell Mol. Med."},{"key":"B49","doi-asserted-by":"publisher","first-page":"e2304480","DOI":"10.1002\/advs.202304480","article-title":"Decoding macrophage subtypes to engineer modulating hydrogels for the alleviation of intervertebral disk degeneration","volume":"11","author":"Zhao","year":"2024","journal-title":"Adv. Sci. (Weinh)"},{"key":"B50","doi-asserted-by":"publisher","first-page":"109739","DOI":"10.1016\/j.mehy.2020.109739","article-title":"Amyloid protein aggregation in diabetes mellitus accelerate intervertebral disc degeneration","volume":"141","author":"Zheng","year":"2020","journal-title":"Med. Hypotheses"}],"container-title":["Frontiers in Bioengineering and Biotechnology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2025.1639117\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T05:24:07Z","timestamp":1754371447000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2025.1639117\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,5]]},"references-count":50,"alternative-id":["10.3389\/fbioe.2025.1639117"],"URL":"https:\/\/doi.org\/10.3389\/fbioe.2025.1639117","relation":{},"ISSN":["2296-4185"],"issn-type":[{"value":"2296-4185","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,5]]},"article-number":"1639117"}}