# Genetics and pathophysiology of diffuse idiopathic skeletal hyperostosis

**Authors:** Wenhao Ji, Wanlei Yang, Shikang Su, Simin Sun, Huanhao Cai, Kangnan Wang, Bin Pan, Yu Qian

PMC · DOI: 10.3389/fendo.2026.1745930 · Frontiers in Endocrinology · 2026-02-17

## TL;DR

This paper reviews the genetic and environmental factors behind a bone condition called DISH, which causes spine issues and is common in older adults.

## Contribution

The paper offers a comprehensive review of recent advances in understanding DISH's genetics, inflammation, metabolism, and animal models.

## Key findings

- DISH is marked by spine ossification and is linked to aging and environmental factors.
- Current research highlights the role of inflammation and metabolism in DISH's development.
- No disease-modifying therapies exist for DISH, and it remains underdiagnosed.

## Abstract

Diffuse Idiopathic Skeletal Hyperostosis (DISH) is a systemic condition primarily characterized by flowing ossification along the anterolateral aspects of the spine, often leading to back pain, dysphagia, and an increased risk of spinal fractures. Despite its significant clinical burden and high prevalence among the elderly, DISH remains underdiagnosed and poorly understood, with no disease-modifying therapies currently available. This article provides a comprehensive review of the genetic variations and environmental factors involved in the pathogenesis of DISH, encompassing recent research progress in inflammation, metabolism, pathogenic genes, and animal models. It also critically highlights the current challenges and future directions in DISH research.

## Linked entities

- **Diseases:** Diffuse Idiopathic Skeletal Hyperostosis (MONDO:0007127)

## Full-text entities

- **Genes:** PPP2R2D (protein phosphatase 2 regulatory subunit Bdelta) [NCBI Gene 55844] {aka B55D, B55delta, MDS026}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, LGALS3 (galectin 3) [NCBI Gene 3958] {aka CBP35, GAL3, GALBP, GALIG, L31, LGALS2}, COL6A6 (collagen type VI alpha 6 chain) [NCBI Gene 131873], PTH (parathyroid hormone) [NCBI Gene 5741] {aka FIH1, PTH1}, BMP2 (bone morphogenetic protein 2) [NCBI Gene 650] {aka BDA2, BMP2A, SSFSC, SSFSC1}, DKK1 (dickkopf Wnt signaling pathway inhibitor 1) [NCBI Gene 22943] {aka DKK-1, SK}, RUNX2 (RUNX family transcription factor 2) [NCBI Gene 860] {aka AML3, CBF-alpha-1, CBFA1, CCD, CCD1, CLCD}, ALPP (alkaline phosphatase, placental) [NCBI Gene 250] {aka ALP, PALP, PLAP, PLAP-1}, IL11 (interleukin 11) [NCBI Gene 3589] {aka AGIF, IL-11}, HNF4A (hepatocyte nuclear factor 4 alpha) [NCBI Gene 3172] {aka FRTS4, HNF4, HNF4a7, HNF4a8, HNF4a9, HNF4alpha}, GGH (gamma-glutamyl hydrolase) [NCBI Gene 8836] {aka GATD10, GH}, ID1 (inhibitor of DNA binding 1) [NCBI Gene 3397] {aka ID, bHLHb24}, BMP4 (bone morphogenetic protein 4) [NCBI Gene 652] {aka BMP2B, BMP2B1, MCOPS6, OFC11, ZYME}, GDF5 (growth differentiation factor 5) [NCBI Gene 8200] {aka BDA1C, BMP-14, BMP14, CDMP1, DUPANS, LAP-4}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 7422] {aka L-VEGF, MVCD1, VEGF, VPF}, RSPO4 (R-spondin 4) [NCBI Gene 343637] {aka C20orf182, CRISTIN4}, GDNF (glial cell derived neurotrophic factor) [NCBI Gene 2668] {aka ATF, ATF1, ATF2, HFB1-GDNF, HSCR3}, ADIPOQ (adiponectin, C1Q and collagen domain containing) [NCBI Gene 9370] {aka ACDC, ACRP30, ADIPQTL1, ADPN, APM-1, APM1}, SOST (sclerostin) [NCBI Gene 50964] {aka CDD, DAND6, SOST1, VBCH}, Slc29a1 (solute carrier family 29 (nucleoside transporters), member 1) [NCBI Gene 63959] {aka 1200014D21Rik, ENT1, mENT1}, INS (insulin) [NCBI Gene 3630] {aka IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10}, IGF1 (insulin like growth factor 1) [NCBI Gene 3479] {aka IGF, IGF-I, IGFI, MGF}, MMP13 (matrix metallopeptidase 13) [NCBI Gene 4322] {aka CLG3, MANDP1, MDST, MMP-13}, ADAMTS5 (ADAM metallopeptidase with thrombospondin type 1 motif 5) [NCBI Gene 11096] {aka ADAM-TS 11, ADAM-TS 5, ADAM-TS5, ADAMTS-11, ADAMTS-5, ADAMTS11}, ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) [NCBI Gene 5167] {aka ARHR2, COLED, M6S1, NPP1, NPPS, PC-1}, ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase 3) [NCBI Gene 5169] {aka B10, CD203c, NPP3, PD-IBETA, PDNP3}, BMP1 (bone morphogenetic protein 1) [NCBI Gene 649] {aka OI13, PCOLC, PCP, TLD}, WNT5A (Wnt family member 5A) [NCBI Gene 7474] {aka hWNT5A}, MSX2 (msh homeobox 2) [NCBI Gene 4488] {aka CRS2, FPP, HOX8, MSH, PFM, PFM1}, SHH (sonic hedgehog signaling molecule) [NCBI Gene 6469] {aka HHG1, HLP3, HPE3, MCOPCB5, SMMCI, ShhNC}, LEP (leptin) [NCBI Gene 3952] {aka LEPD, OB, OBS}, HLA-A (major histocompatibility complex, class I, A) [NCBI Gene 3105] {aka HLAA}, GH1 (growth hormone 1) [NCBI Gene 2688] {aka GH, GH-N, GHB5, GHN, IGHD1A, IGHD1B}, NOG (noggin) [NCBI Gene 9241] {aka SYM1, SYNS1, SYNS1A}, CRP (C-reactive protein) [NCBI Gene 1401] {aka PTX1}, TWIST1 (twist family bHLH transcription factor 1) [NCBI Gene 7291] {aka ACS3, BPES2, BPES3, CRS, CRS1, CSO}, IL17A (interleukin 17A) [NCBI Gene 3605] {aka CTLA-8, CTLA8, IL-17, IL-17A, IL17, ILA17}, COL6A1 (collagen type VI alpha 1 chain) [NCBI Gene 1291] {aka BTHLM1, BTHLM1A, OPLL, UCHMD1, UCHMD1A}, PTPA (protein phosphatase 2 phosphatase activator) [NCBI Gene 5524] {aka PARK25, PP2A, PPP2R4, PR53}, ACVR1 (activin A receptor type 1) [NCBI Gene 90] {aka ACTRI, ACVR1A, ACVRLK2, ALK2, FOP, SKR1}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, FGF2 (fibroblast growth factor 2) [NCBI Gene 2247] {aka BFGF, FGF-2, FGFB, HBGF-2}, CTNNB1 (catenin beta 1) [NCBI Gene 1499] {aka CTNNB, EVR7, MRD19, NEDSDV, armadillo}, DCN (decorin) [NCBI Gene 1634] {aka CSCD, DSPG2, PG40, PGII, PGS2, SLRR1B}, PBX1 (PBX homeobox 1) [NCBI Gene 5087] {aka CAKUHED}
- **Diseases:** sclerosis (MESH:D012598), HO (MESH:D009999), Obesity (MESH:D009765), SpA (MESH:D013167), autosomal dominant disorder (MESH:D030342), Metabolic disorders (MESH:D008659), OA (MESH:D010003), airway obstruction (MESH:D000402), metabolic dysregulation (MESH:D021081), ankylosis (MESH:D000844), heterotopic bone formation (MESH:D058426), ossification of spinal ligament (MESH:D017887), visceral adiposity (MESH:D007418), fatty (MESH:D008067), Inflammation (MESH:D007249), spinal fractures (MESH:D016103), metabolic disturbances (MESH:D024821), visceral fat dysfunction (MESH:C536329), spinal pain and stiffness (MESH:D010146), fractures (MESH:D050723), calcification (MESH:D002114), diabetes (MESH:D003920), impaired glucose metabolism (MESH:D044882), BME (MESH:D004487), ectopic bone formation (MESH:D000072717), musculoskeletal disorders (MESH:D009140), ectopic mineralization (MESH:C537337), NIDDM (MESH:D003924), degenerative disc (MESH:D055959), ossified (MESH:D018214), visceral obesity (MESH:D056128), Bethlem myopathy (MESH:C535436), CC (MESH:D002805), acne (MESH:D000152), bone hyperplasia (MESH:D006965), OSL (MESH:D000082122), arthritis (MESH:D001168), dysphagia (MESH:D003680), DISH (MESH:D004057), calcification of the Achilles tendon (MESH:D052256), hyperinsulinemia (MESH:D006946), intervertebral disc destruction (MESH:C535531), back pain (MESH:D001416), axial spondyloarthritis (MESH:D000089183), joint (MESH:D007592), bone (MESH:D001847), bone erosion (MESH:D014077), insulin resistance (MESH:D007333), nerve tissue damage (MESH:D009380)
- **Chemicals:** adenosine (MESH:D000241), phosphate (MESH:D010710), Isotretinoin (MESH:D015474), inorganic pyrophosphate (-), hydroxyapatite (MESH:D017886)
- **Species:** Mus musculus (house mouse, species) [taxon 10090], Canis lupus familiaris (dog, subspecies) [taxon 9615], Homo sapiens (human, species) [taxon 9606]
- **Mutations:** rs201930700, rs145135062, rs2241716, rs3747676, rs34473884, p.K400E, rs149154047, Y433C, rs4252548, rs1476217, rs146447064, rs2236486, c.1352A>G, rs200963433, serine/threonine

## Full text

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## Figures

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## References

120 references — full list in the complete paper: https://tomesphere.com/paper/PMC12953109/full.md

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Source: https://tomesphere.com/paper/PMC12953109