The possible role of hypoxia in the affected tissue of relapsed clubfoot
Language English Country England, Great Britain Media electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
35292718
PubMed Central
PMC8924187
DOI
10.1038/s41598-022-08519-z
PII: 10.1038/s41598-022-08519-z
Knihovny.cz E-resources
- MeSH
- Hemoglobin Subunits MeSH
- Hypoxia complications genetics MeSH
- Humans MeSH
- Matrix Metalloproteinase 2 genetics MeSH
- Clubfoot * genetics MeSH
- Recurrence MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Hemoglobin Subunits MeSH
- Matrix Metalloproteinase 2 MeSH
Our aim was to study the expression of hypoxia-related proteins as a possible regulatory pathway in the contracted side tissue of relapsed clubfoot. We compared the expression of hypoxia-related proteins in the tissue of the contracted (medial) side of relapsed clubfoot, and in the tissue of the non-contracted (lateral) side of relapsed clubfoot. Tissue samples from ten patients were analyzed by immunohistochemistry and image analysis, Real-time PCR and Mass Spectrometry to evaluate the differences in protein composition and gene expression. We found a significant increase in the levels of smooth muscle actin, transforming growth factor-beta, hypoxia-inducible factor 1 alpha, lysyl oxidase, lysyl oxidase-like 2, tenascin C, matrix metalloproteinase-2, matrix metalloproteinase-9, fibronectin, collagen types III and VI, hemoglobin subunit alpha and hemoglobin subunit beta, and an overexpression of ACTA2, FN1, TGFB1, HIF1A and MMP2 genes in the contracted medial side tissue of clubfoot. In the affected tissue, we have identified an increase in the level of hypoxia-related proteins, together with an overexpression of corresponding genes. Our results suggest that the hypoxia-associated pathway is potentially a factor contributing to the etiology of clubfoot relapses, as it stimulates both angioproliferation and fibroproliferation, which are considered to be key factors in the progression and development of relapses.
2nd Faculty of Medicine Charles University Prague Czech Republic
Department of Orthopaedics University Hospital Bulovka Charles University Prague Czech Republic
Faculty of Physical Education and Sport Charles University Prague Czech Republic
Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic
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Pavone V, et al. The etiology of idiopathic congenital talipes equinovarus: a systematic review. J. Orthop. Surg. Res. 2018;13:206. doi: 10.1186/s13018-018-0913-z. PubMed DOI PMC
Ansar A, et al. Systematic review and meta-analysis of global birth prevalence of clubfoot: a study protocol. BMJ Open. 2018;8:e019246. doi: 10.1136/bmjopen-2017-019246. PubMed DOI PMC
Dobbs MB, Gurnett CA. Update on Clubfoot: Etiology and treatment. Clin. Orthop. Relat. Res. 2009;467:1146–1153. doi: 10.1007/s11999-009-0734-9. PubMed DOI PMC
Hosseinzadeh P, Kiebzak G, Dolan L, Zionts L, Morcuende J. Management of clubfoot relapses with the ponseti method: Results of a survey of the POSNA members. J. Pediatr. Orthop. 2019;39:38–41. doi: 10.1097/BPO.0000000000000953. PubMed DOI
Dobbs MB, et al. Factors predictive of outcome after use of the Ponseti method for the treatment of idiopathic clubfeet. J. Bone Joint. Surg. Am. 2004;86:22–27. doi: 10.2106/00004623-200401000-00005. PubMed DOI
Li C, Nguyen Q, Cole WG, Alman BA. Potential treatment for clubfeet based on growth factor blockade. J. Pediatr. Orthop. 2001;21:372–377. PubMed
Eckhardt A, et al. Novel contribution to clubfoot pathogenesis: The possible role of extracellular matrix proteins. J. Orthop. Res. 2019;37:769–778. doi: 10.1002/jor.24211. PubMed DOI
Novotny T, et al. Increased microvessel and arteriole density in the contracted side of the relapsed clubfoot. J. Pediatr. Orthop. 2020;40:592–596. doi: 10.1097/BPO.0000000000001563. PubMed DOI
Holzer LA, Cör A, Pfandlsteiner G, Holzer G. Expression of VEGF, its receptors, and HIF-1α in Dupuytren’s disease. Acta Orthop. 2013;84:420–425. doi: 10.3109/17453674.2013.814011. PubMed DOI PMC
Krakhotkin DV, Chernylovskyi VA, Mottrie A, Greco F, Bugaev RA. New insights into the pathogenesis of Peyronie’s disease: A narrative review. Chronic Dis. Transl. Med. 2020;6:165–181. doi: 10.1016/j.cdtm.2020.06.001. PubMed DOI PMC
Haase VH. Hypoxia-inducible factor signaling in the development of kidney fibrosis. Fibrogenesis Tissue Repair. 2012;5:S16. doi: 10.1186/1755-1536-5-S1-S16. PubMed DOI PMC
Cai J, Hu M, Chen Z, Ling Z. The roles and mechanisms of hypoxia in liver fibrosis. J. Transl. Med. 2021;19:186. doi: 10.1186/s12967-021-02854-x. PubMed DOI PMC
Chen P-S, et al. Pathophysiological implications of hypoxia in human diseases. J. Biomed. Sci. 2020;27:63. doi: 10.1186/s12929-020-00658-7. PubMed DOI PMC
Knitlova J, et al. Increased collagen crosslinking in stiff clubfoot tissue: Implications for the improvement of therapeutic strategies. Int. J. Mol. Sci. 2021;22:11903. doi: 10.3390/ijms222111903. PubMed DOI PMC
Shabtai L, Specht SC, Herzenberg JE. Worldwide spread of the Ponseti method for clubfoot. World J. Orthop. 2014;5:585–590. doi: 10.5312/wjo.v5.i5.585. PubMed DOI PMC
Ponseti IV. Relapsing clubfoot: Causes, prevention, and treatment. Iowa Orthop. J. 2002;22:55–56. PubMed PMC
Iyer NV, et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α. Genes Dev. 1998;12:149–162. doi: 10.1101/gad.12.2.149. PubMed DOI PMC
Novotný T, et al. Mast cell stabilization with sodium cromoglycate modulates pulmonary vessel wall remodeling during four-day hypoxia in rats. Exp. Lung Res. 2015;41:283–292. doi: 10.3109/01902148.2015.1018558. PubMed DOI
Novotný T, Uhlík J, Vajner L. Four-day pulse of sodium cromoglycate modulates pulmonary vessel wall remodeling during 21-day hypoxia in rats. Exp. Lung. Res. 2018;44:1–12. doi: 10.1080/01902148.2017.1393708. PubMed DOI
Misra S, Shergill U, Yang B, Janardhanan R, Misra KD. Increased expression of HIF-1alpha, VEGF-A and its receptors, MMP-2, TIMP-1, and ADAMTS-1 at the venous stenosis of arteriovenous fistula in a mouse model with renal insufficiency. J. Vasc. Interv. Radiol. 2010;21:1255–1261. doi: 10.1016/j.jvir.2010.02.043. PubMed DOI PMC
Biswas S, et al. CD31 angiogenesis and combined expression of HIF-1α and HIF-2α are prognostic in primary clear-cell renal cell carcinoma (CC-RCC), but HIFα transcriptional products are not: Implications for antiangiogenic trials and HIFα biomarker studies in primary CC-RCC. Carcinogenesis. 2012;33:1717–1725. doi: 10.1093/carcin/bgs222. PubMed DOI
Liu Y, et al. MMP-2 and MMP-9 contribute to the angiogenic effect produced by hypoxia/15-HETE in pulmonary endothelial cells. J. Mol. Cell Cardiol. 2018;121:36–50. doi: 10.1016/j.yjmcc.2018.06.006. PubMed DOI
Wang X, Khalil RA. Matrix metalloproteinases, vascular remodeling, and vascular disease. Adv. Pharmacol. 2018;81:241–330. doi: 10.1016/bs.apha.2017.08.002. PubMed DOI PMC
Karsdal MA, et al. The good and the bad collagens of fibrosis: Their role in signaling and organ function. Adv. Drug Deliv. Rev. 2017;121:43–56. doi: 10.1016/j.addr.2017.07.014. PubMed DOI
Ottino P, et al. Hypoxia activates matrix metalloproteinase expression and the VEGF system in monkey choroid-retinal endothelial cells: Involvement of cytosolic phospholipase A2 activity. Mol. Vis. 2004;10:341–350. PubMed
Žaloudíková M, et al. Decreased collagen VI in the tunica media of pulmonary vessels during exposure to hypoxia: A novel step in pulmonary arterial remodeling. Pulm. Circ. 2019 doi: 10.1177/2045894019860747. PubMed DOI PMC
Chelladurai P, Seeger W, Pullamsetti SS. Matrix metalloproteinases and their inhibitors in pulmonary hypertension. Eur. Respir. J. 2012;40:766–782. doi: 10.1183/09031936.00209911. PubMed DOI
Newby AC. Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading matrix and non-matrix substrates. Cardiovasc. Res. 2006;69:614–624. doi: 10.1016/j.cardiores.2005.08.002. PubMed DOI
Mallikarjuna P, Raviprakash T, Aripaka K, Ljungberg B, Landström M. Interactions between TGF-β type I receptor and hypoxia-inducible factor-α mediates a synergistic crosstalk leading to poor prognosis for patients with clear cell renal cell carcinoma. Cell Cycle. 2019;18:1–16. doi: 10.1080/15384101.2019.1642069. PubMed DOI PMC
Biernacka A, Dobaczewski M, Frangogiannis NG. TGF-β signaling in fibrosis. Growth Factors. 2011;29:196–202. doi: 10.3109/08977194.2011.595714. PubMed DOI PMC
Shinde AV, Humeres C, Frangogiannis NG. The role of α-smooth muscle actin in fibroblast-mediated matrix contraction and remodeling. Biochim. Biophys. Acta Mol. Basis Dis. 2017;1863:298–309. doi: 10.1016/j.bbadis.2016.11.006. PubMed DOI PMC
Bochaton-Piallat M-L, Gabbiani G, Hinz B. The myofibroblast in wound healing and fibrosis: Answered and unanswered questions. F1000 Res. 2016;5:752. doi: 10.12688/f1000research.8190.1. PubMed DOI PMC
Bielefeld KA, et al. Fibronectin and beta-catenin act in a regulatory loop in dermal fibroblasts to modulate cutaneous healing. J. Biol. Chem. 2011;286:27687–27697. doi: 10.1074/jbc.M111.261677. PubMed DOI PMC
Kim K, et al. β-Catenin overexpression augments angiogenesis and skeletal muscle regeneration through dual mechanism of vascular endothelial growth factor-mediated endothelial cell proliferation and progenitor cell mobilization. Arterioscler. Thromb. Vasc. Biol. 2006;26:91–98. doi: 10.1161/01.ATV.0000193569.12490.4b. PubMed DOI
Kasprzycka M, Hammarström C, Haraldsen G. Tenascins in fibrotic disorders: From bench to bedside. Cell Adher. Migr. 2015;9:83–89. doi: 10.4161/19336918.2014.994901. PubMed DOI PMC
Schietke R, et al. The lysyl oxidases LOX and LOXL2 are necessary and sufficient to repress e-cadherin in hypoxia: Insights into cellular transformation processes mediated by HIF-1. J. Biol. Chem. 2010;285:6658–6669. doi: 10.1074/jbc.M109.042424. PubMed DOI PMC
Higgins DF, et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J. Clin. Invest. 2007;117:3810–3820. doi: 10.1172/JCI30487. PubMed DOI PMC
Levental KR, et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 2009;139:891–906. doi: 10.1016/j.cell.2009.10.027. PubMed DOI PMC
Pez F, et al. The HIF-1-inducible lysyl oxidase activates HIF-1 via the Akt pathway in a positive regulation loop and synergizes with HIF-1 in promoting tumor cell growth. Cancer Res. 2011;71:1647–1657. doi: 10.1158/0008-5472.CAN-10-1516. PubMed DOI
Barker HE, Cox TR, Erler JT. The rationale for targeting the LOX family in cancer. Nat. Rev. Cancer. 2012;12:540–552. doi: 10.1038/nrc3319. PubMed DOI
Grek CL, Newton DA, Spyropoulos DD, Baatz JE. Hypoxia up-regulates expression of hemoglobin in alveolar epithelial cells. Am. J. Respir. Cell Mol. Biol. 2011;44:439–447. doi: 10.1165/rcmb.2009-0307OC. PubMed DOI PMC
Butcher JT, Johnson T, Beers J, Columbus L, Isakson BE. Hemoglobin α in the blood vessel wall. Free Radic. Biol. Med. 2014;73:136–142. doi: 10.1016/j.freeradbiomed.2014.04.019. PubMed DOI PMC
Maman S, et al. The beta subunit of hemoglobin (HBB2/HBB) suppresses neuroblastoma growth and metastasis. Cancer Res. 2017;77:14–26. doi: 10.1158/0008-5472. PubMed DOI
Ponzetti M, et al. Non-conventional role of haemoglobin beta in breast malignancy. Br. J. Cancer. 2017;117:994–1006. doi: 10.1038/bjc.2017.247. PubMed DOI PMC
Cai G, et al. Integrated bioinformatics analysis of potential pathway biomarkers using abnormal proteins in clubfoot. PeerJ. 2020;8:e8422. doi: 10.7717/peerj.8422. PubMed DOI PMC
Satish L, et al. Developing an animal model of Dupuytren’s disease by orthotopic transplantation of human fibroblasts into athymic rat. BMC Musculoskelet. Disord. 2015;16:138. doi: 10.1186/s12891-015-0597-z. PubMed DOI PMC
Nanchahal J, et al. Anti-tumour necrosis factor therapy for Dupuytren’s disease: A randomised dose response proof of concept phase 2a clinical trial. EBioMedicine. 2018;33:282–288. doi: 10.1016/j.ebiom.2018.06.022. PubMed DOI PMC
Knitlova J, et al. Minoxidil decreases collagen I deposition and tissue-like contraction in clubfoot-derived cells: A way to improve conservative treatment of relapsed clubfoot? Connect. Tissue Res. 2021;62:554–569. doi: 10.1080/03008207.2020.1816992. PubMed DOI
Johnson SJ, Walker FR. Strategies to improve quantitative assessment of immunohistochemical and immunofluorescent labelling. Sci. Rep. 2015;5:10607. doi: 10.1038/srep10607. PubMed DOI PMC
