# Glycolytic reprogramming mediated by the ADAM12/IGF1 axis promotes ossification of the posterior longitudinal ligament **Authors:** Qi Zhao, Hao Wu, Dong Xie, Mingliang Shi, Baocheng Niu, Lili Yang PMC · DOI: 10.1038/s41420-026-03044-8 · Cell Death Discovery · 2026-03-25 ## TL;DR This study reveals that a metabolic shift driven by ADAM12 and IGF1 promotes abnormal bone formation in a spinal disorder called OPLL. ## Contribution The discovery of the ADAM12/IGF1 axis as a novel driver of glycolytic reprogramming in OPLL pathogenesis. ## Key findings - Enhanced glycolysis and suppressed oxidative phosphorylation are critical for osteogenic differentiation in OPLL. - ADAM12 activates IGF1 signaling via IGFBP5 modulation to drive glycolytic flux and osteogenesis. - Inhibiting ADAM12, IGF1R, or glycolysis reverses pro-ossific effects in OPLL models. ## Abstract Ossification of the posterior longitudinal ligament (OPLL) is a debilitating spinal disorder characterized by heterotopic bone formation and severe neurological deficits, yet its underlying pathogenic mechanisms remain poorly understood. Here, we report that glycolytic reprogramming orchestrated by the ADAM12/IGF1 axis is a critical driver of OPLL pathogenesis. Through integrated multi-omics analysis of human OPLL tissues, we uncovered a profound metabolic shift featuring enhanced glycolysis and suppressed oxidative phosphorylation as ligament progenitor cells differentiated into osteoblasts. This glycolytic reprogramming was functionally indispensable for ossification, as its inhibition with 2-deoxy-D-glucose robustly attenuated osteogenic differentiation in vitro and ectopic bone formation in vivo. We identified ADAM12 as a pivotal upstream regulator that is highly upregulated in OPLL. Mechanistically, ADAM12 activates the IGF1 signaling pathway by modulating IGFBP5, which in turn drives glycolytic flux and lactate production to fuel the osteogenic differentiation of ligament cells. Crucially, the pro-ossific effects of ADAM12 were reversed by inhibition of either IGF1R or glycolysis. Taken together, our study establishes the ADAM12-IGF1-glycolysis axis as a central pathogenic mechanism and a promising therapeutic target for OPLL. ## Linked entities - **Genes:** ADAM12 (ADAM metallopeptidase domain 12) [NCBI Gene 8038], IGF1 (insulin like growth factor 1) [NCBI Gene 3479], IGFBP5 (insulin like growth factor binding protein 5) [NCBI Gene 3488], IGF1R (insulin like growth factor 1 receptor) [NCBI Gene 3480] - **Chemicals:** 2-deoxy-D-glucose (PubChem CID 108223) - **Diseases:** OPLL (MONDO:0011230) ## Full-text entities - **Genes:** LDHA (lactate dehydrogenase A) [NCBI Gene 3939] {aka GSD11, HEL-S-133P, LDHM, PIG19}, ALPP (alkaline phosphatase, placental) [NCBI Gene 250] {aka ALP, PALP, PLAP, PLAP-1}, TFAM (transcription factor A, mitochondrial) [NCBI Gene 7019] {aka MTDPS15, MTTF1, MTTFA, TCF6, TCF6L1, TCF6L2}, LYZ (lysozyme) [NCBI Gene 4069] {aka AMYLD5, LYZF1, LZM}, PDK1 (pyruvate dehydrogenase kinase 1) [NCBI Gene 5163], S100A9 (S100 calcium binding protein A9) [NCBI Gene 6280] {aka 60B8AG, CAGB, CFAG, CGLB, L1AG, LIAG}, Igf1 (insulin-like growth factor 1) [NCBI Gene 16000] {aka C730016P09Rik, Igf-1, Igf-I}, PRG4 (proteoglycan 4) [NCBI Gene 10216] {aka CACP, HAPO, JCAP, MSF, SZP}, HK1 (hexokinase 1) [NCBI Gene 3098] {aka CNSHA5, HK, HK1-ta, HK1-tb, HK1-tc, HKD}, Runx2 (runt related transcription factor 2) [NCBI Gene 12393] {aka AML3, CBF-alpha-1, Cbf, Cbfa-1, Cbfa1, LS3}, Sp7 (Sp7 transcription factor 7) [NCBI Gene 170574] {aka 6430578P22Rik, C22, Osx}, SLC2A1 (solute carrier family 2 member 1) [NCBI Gene 6513] {aka CSE, DYT17, DYT18, DYT9, EIG12, GLUT}, S100A8 (S100 calcium binding protein A8) [NCBI Gene 6279] {aka 60B8AG, CAGA, CFAG, CGLA, CP-10, L1Ag}, PTH (parathyroid hormone) [NCBI Gene 5741] {aka FIH1, PTH1}, VIM (vimentin) [NCBI Gene 7431], DCN (decorin) [NCBI Gene 1634] {aka CSCD, DSPG2, PG40, PGII, PGS2, SLRR1B}, IGFBP3 (insulin like growth factor binding protein 3) [NCBI Gene 3486] {aka BP-53, IBP-3, IBP3, IGFBP-3}, TIMP2 (TIMP metallopeptidase inhibitor 2) [NCBI Gene 7077] {aka CSC-21K, DDC8}, POTEF (POTE ankyrin domain family member F) [NCBI Gene 728378] {aka A26C1B, POTE2alpha, POTEACTIN}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, alp (alopecia, recessive) [NCBI Gene 11691], IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, BGLAP (bone gamma-carboxyglutamate protein) [NCBI Gene 632] {aka BGP, OC, OCN}, RUNX2 (RUNX family transcription factor 2) [NCBI Gene 860] {aka AML3, CBF-alpha-1, CBFA1, CCD, CCD1, CLCD}, PECAM1 (platelet and endothelial cell adhesion molecule 1) [NCBI Gene 5175] {aka CD31, CD31/EndoCAM, GPIIA', PECA1, PECAM-1, endoCAM}, PPARGC1A (PPARG coactivator 1 alpha) [NCBI Gene 10891] {aka LEM6, PGC-1(alpha), PGC-1alpha, PGC-1v, PGC1, PGC1A}, ADAM12 (ADAM metallopeptidase domain 12) [NCBI Gene 8038] {aka ADAM12-OT1, CAR10, MCMP, MCMPMltna, MLTN, MLTNA}, Bmp2 (bone morphogenetic protein 2) [NCBI Gene 12156] {aka Bmp2a}, IGF1 (insulin like growth factor 1) [NCBI Gene 3479] {aka IGF, IGF-I, IGFI, MGF}, Adam12 (ADAM metallopeptidase domain 12) [NCBI Gene 11489] {aka 5830403F22Rik, Mltna}, Igf1r (insulin-like growth factor I receptor) [NCBI Gene 16001] {aka A330103N21Rik, CD221, D930020L01, IGF-1R, hyft}, Slurp1 (secreted Ly6/Plaur domain containing 1) [NCBI Gene 57277] {aka 1110021N19Rik, ARS, ArsB, Slurp-1}, Pecam1 (platelet/endothelial cell adhesion molecule 1) [NCBI Gene 18613] {aka Cd31, PECAM-1, Pecam}, PKM (pyruvate kinase M1/2) [NCBI Gene 5315] {aka CTHBP, HEL-S-30, OIP3, PK3, PKM2, TCB}, SP7 (Sp7 transcription factor) [NCBI Gene 121340] {aka OI11, OI12, OSX, osterix}, RGS5 (regulator of G protein signaling 5) [NCBI Gene 8490] {aka MST092, MST106, MST129, MSTP032, MSTP092, MSTP106}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 7422] {aka L-VEGF, MVCD1, VEGF, VPF}, IGF1R (insulin like growth factor 1 receptor) [NCBI Gene 3480] {aka CD221, IGFIR, IGFR, JTK13}, ACAN (aggrecan) [NCBI Gene 176] {aka AGC1, AGCAN, CSPG1, CSPGCP, MSK16, SEDK}, IGFBP5 (insulin like growth factor binding protein 5) [NCBI Gene 3488] {aka IBP5}, HK2 (hexokinase 2) [NCBI Gene 3099] {aka HKII, HXK2}, ACTA2 (actin alpha 2, smooth muscle) [NCBI Gene 59] {aka ACTSA, SMDYS}, JCHAIN (joining chain of multimeric IgA and IgM) [NCBI Gene 3512] {aka IGCJ, IGJ, JCH}, IGFBP6 (insulin like growth factor binding protein 6) [NCBI Gene 3489] {aka IBP6}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, MS4A1 (membrane spanning 4-domains A1) [NCBI Gene 931] {aka B1, Bp35, CD20, CVID5, FMC7, LEU-16}, Prg4 (proteoglycan 4 (megakaryocyte stimulating factor, articular superficial zone protein)) [NCBI Gene 96875] {aka CACP, DOL54, JCAP, MSF, SZP, lubricin}, THBS1 (thrombospondin 1) [NCBI Gene 7057] {aka THBS, THBS-1, TSP, TSP-1, TSP1}, ATP5PF (ATP synthase peripheral stalk subunit F6) [NCBI Gene 522] {aka ATP5, ATP5A, ATP5J, ATPM, CF6, F6}, CD68 (CD68 molecule) [NCBI Gene 968] {aka GP110, LAMP4, SCARD1}, Pkm (pyruvate kinase, muscle) [NCBI Gene 18746] {aka Pk-2, Pk-3, Pk3, Pkm2}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, MMP1 (matrix metallopeptidase 1) [NCBI Gene 4312] {aka CLG}, CYCS (cytochrome c, somatic) [NCBI Gene 54205] {aka CYC, HCS, THC4}, FGF2 (fibroblast growth factor 2) [NCBI Gene 2247] {aka BFGF, FGF-2, FGFB, HBGF-2}, CD3E (CD3 epsilon subunit of T-cell receptor complex) [NCBI Gene 916] {aka CD3epsilon, IMD18, T3E, TCRE}, COL3A1 (collagen type III alpha 1 chain) [NCBI Gene 1281] {aka EDS4A, EDSVASC, PMGEDSV}, BLNK (B cell linker) [NCBI Gene 29760] {aka AGM4, BASH, BLNK-S, LY57, SLP-65, SLP65} - **Diseases:** heterotopic bone formation (MESH:D058426), quadriplegia (MESH:D011782), spinal canal stenosis (MESH:D013130), incontinence (MESH:D014549), ossified (MESH:D018214), ectopic ossification (MESH:D009999), diabetes (MESH:D003920), spinal disorder (MESH:D013118), ossification (MESH:C562735), degenerative cervical spine conditions (MESH:D019636), ectopic bone formation (MESH:D000072717), neurological deficits (MESH:D009461), systemic diseases (MESH:D034721), ligament degeneration (MESH:D009410), radiculopathy (MESH:D011843), inflammatory (MESH:D007249), cervical spondylotic myelopathy (MESH:D002575), OPLL (MESH:D017887), fibro-osseous disorders (MESH:D009810), cancer (MESH:D009369) - **Chemicals:** DAPI (MESH:C007293), SDS (MESH:D012967), paraformaldehyde (MESH:C003043), GSK2837808A (MESH:C000612070), EDTA (MESH:D004492), K, (MESH:D011188), dexamethasone (MESH:D003907), oligomycin (MESH:D009840), rotenone (MESH:D012402), 2-DG (MESH:D003847), streptomycin (MESH:D013307), PVDF (MESH:C024865), calcium (MESH:D002118), citrate (MESH:D019343), Bio-Oss Collagen (-), polybrene (MESH:D006583), Linsitinib (MESH:C551528), carbon (MESH:D002244), Rapamycin (MESH:D020123), Lactate (MESH:D019344), beta-glycerophosphate (MESH:C031463), Triton X-100 (MESH:D017830), oxygen (MESH:D010100), pyruvate (MESH:D019289), ATP (MESH:D000255), 3-phosphoglycerate (MESH:C005156), CO2 (MESH:D002245), carbohydrate (MESH:D002241), ascorbic acid (MESH:D001205), PEP (MESH:D010728), antimycin A (MESH:D000968), Alizarin Red S (MESH:C004468), Glucose (MESH:D005947), fructose-1,6-bisphosphate (MESH:C029063), ROS (MESH:D017382), paraffin (MESH:D010232), isoflurane (MESH:D007530), FCCP (MESH:D002259), DCFH-DA (MESH:C029569), penicillin (MESH:D010406) - **Species:** Homo sapiens (human, species) [taxon 9606], Mus musculus (house mouse, species) [taxon 10090], Mycoplasma (genus) [taxon 2093] - **Mutations:** C2001S, P0321S, glutamine (Q) at amino acid 351 - **Cell lines:** BALB/c — Mus musculus (Mouse), Spontaneously immortalized cell line (CVCL_0184), OPLL — Homo sapiens (Human), Multifocal osteosarcoma, Cancer cell line (CVCL_6E83), OPLL ligament — Homo sapiens (Human), Telomerase immortalized cell line (CVCL_C3S0), PLL — Homo sapiens (Human), Adult T-cell leukemia/lymphoma, Cancer cell line (CVCL_B7JH), /6J — Homo sapiens (Human), Cutaneous melanoma, Cancer cell line (CVCL_W797) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC13039164/full.md ## Figures 9 figures with captions in the complete paper: https://tomesphere.com/paper/PMC13039164/full.md --- Source: https://tomesphere.com/paper/PMC13039164