Hypoxia can cause basement membrane (BM) degradation in tissues. Matrix metalloproteinase 9 (MMP-9) is involved in various human cancers as well as BM degradation by downregulating type IV collagen (COL4). This study investigated the role of MMP-9 in hypoxia-mediated BM degradation in rat bone marrow based on its regulation of collagen type IV alpha 1 chain (COL4A1). Eighty male rats were randomly divided into four groups based on exposure to hypoxic conditions at a simulated altitude of 7,000 m, control (normoxia) and 3, 7, and 10 days of hypoxia exposure. BM degradation in bone marrow was determined by transmission electron microscopy. MMP-9 levels were assessed by western blot and real-time PCR, and COL4A1 levels were assessed by western blot and immunohistochemistry. Microvessels BMs in bone marrow exposed to acute hypoxia were observed by electron microscopy. MMP-9 expression increased, COL4A1 protein expression decreased, and BM degradation occurred in the 10-, 7-, and 3-day hypoxia groups compared with that in the control group (all P < 0.05). Hypoxia increased MMP-9 levels, which in turn downregulated COL4A1, thereby increasing BM degradation. MMP-9 upregulation significantly promoted BM degradation and COL4A1 downregulation. Our results suggest that MMP-9 is related to acute hypoxia-induced BM degradation in bone marrow by regulating COL4A1.

Affiliated Hospital of Qinghai University Xining China;

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MacIntyre NR. Tissue hypoxia: implications for the respiratory clinician. Respir Care. 2014;59(10):1590–1596. doi: 10.4187/respcare.03357. PubMed DOI

Su J, Li Z, Cui S, Ji L, Geng H, Chai K, Ma X, Bai Z, Yang Y, Wuren T. The Local HIF-2α/EPO Pathway in the Bone Marrow is Associated with Excessive Erythrocytosis and the Increase in Bone Marrow Microvessel Density in Chronic Mountain Sickness. High Alt Med Biol. 2015;16(4):318–330. doi: 10.1089/ham.2015.0015. PubMed DOI PMC

Lee SH, Manandhar S, Lee YM. Roles of RUNX in Hypoxia-Induced Responses and Angiogenesis. Adv Exp Med Biol. 2017;962:449–469. doi: 10.1007/978-981-10-3233-2_27. PubMed DOI

Leach RM, Treacher DF. Oxygen transport-2. Tissue hypoxia. Bmj. 1998;317(7169):1370–1373. doi: 10.1136/bmj.317.7169.1370. PubMed DOI PMC

Martin DS, Khosravi M, Grocott MP, Mythen MG. Concepts in hypoxia reborn. Crit Care. 2010;14(4):315. doi: 10.1186/cc9078. PubMed DOI PMC

Berger MM, Grocott MPW. Facing acute hypoxia: from the mountains to critical care medicine. Br J Anaesth. 2017;118(3):283–286. doi: 10.1093/bja/aew407. PubMed DOI

Prokudina ES, Naryzhnaya NV, Mukhomedzyanov AV, Gorbunov AS, Zhang Y, Yaggi AS, Tsibulnikov SY, Nesterov EA, Lishmanov YB, Suleiman MS. Effect of Chronic Continuous Normobaric Hypoxia on Functional State of Cardiac Mitochondria and Tolerance of Isolated Rat Heart to Ischemia and Reperfusion: Role of μ and delta2 Opioid Receptors. Physiol Res. 2019;68(6):909–920. doi: 10.33549/physiolres.933945. PubMed DOI

Honda J, Kimura T, Sakai S, Maruyama H, Tajiri K, Murakoshi N, Homma S, Miyauchi T, Aonuma K. The glucagon-like peptide-1 receptor agonist liraglutide improves hypoxia-induced pulmonary hypertension in mice partly via normalization of reduced ET(B) receptor expression. Physiol Res. 2018;67(Suppl 1):S175–s184. doi: 10.33549/physiolres.933822. PubMed DOI

Wang Y, Ai L, Hai B, Cao Y, Li R, Li H, Li Y. Tempol alleviates chronic intermittent hypoxia-induced pancreatic injury through repressing inflammation and apoptosis. Physiol Res. 2019;68(3):445–455. doi: 10.33549/physiolres.934010. PubMed DOI

Kolesnikov SI, Popova AS, Krupitskaya LI, Sinitskii AI, Kolesnikova LI. Activity of Heme Synthesis Enzymes in the Bone Marrow and Liver of August and Wistar Rats During the Neonatal Period and After Acute Postnatal Hypoxia. Bull Exp Biol Med. 2015;160(2):193–195. doi: 10.1007/s10517-015-3125-0. PubMed DOI

Andreeva E, Matveeva D. Multipotent mesenchymal stromal cells and extracellular matrix: regulation under hypoxia. Human Physiology. 2018;44(6):696–705. doi: 10.1134/S0362119718060038. DOI

Misko A, Ferguson T, Notterpek L. Matrix metalloproteinase mediated degradation of basement membrane proteins in Trembler J neuropathy nerves. J Neurochem. 2002;83(4):885–894. doi: 10.1046/j.1471-4159.2002.01200.x. PubMed DOI

Hou H, Zhang G, Wang H, Gong H, Wang C, Zhang X. High matrix metalloproteinase-9 expression induces angiogenesis and basement membrane degradation in stroke-prone spontaneously hypertensive rats after cerebral infarction. Neural Regen Res. 2014;9(11):1154–1162. doi: 10.4103/1673-5374.135318. PubMed DOI PMC

Huang H. Matrix Metalloproteinase-9 (MMP-9) as a Cancer Biomarker and MMP-9 Biosensors: Recent Advances. Sensors (Basel) 2018;18(10) doi: 10.3390/s18103249. PubMed DOI PMC

Lochter A, Sternlicht MD, Werb Z, Bissell MJ. The significance of matrix metalloproteinases during early stages of tumor progression. Ann N Y Acad Sci. 1998;857:180–193. doi: 10.1111/j.1749-6632.1998.tb10116.x. PubMed DOI

Hlobilkova A, Ehrmann J, Knizetova P, Krejci V, Kalita O, Kolar Z. Analysis of VEGF, Flt-1, Flk-1, nestin and MMP-9 in relation to astrocytoma pathogenesis and progression. Neoplasma. 2009;56(4):284–290. doi: 10.4149/neo_2009_04_284. PubMed DOI

Radenkovic S, Konjevic G, Jurisic V, Karadzic K, Nikitovic M, Gopcevic K. Values of MMP-2 and MMP-9 in tumor tissue of basal-like breast cancer patients. Cell Biochem Biophys. 2014;68(1):143–152. doi: 10.1007/s12013-013-9701-x. PubMed DOI

Yang JS, Lin CW, Hsieh YS, Cheng HL, Lue KH, Yang SF, Lu KH. Selaginella tamariscina (Beauv.) possesses antimetastatic effects on human osteosarcoma cells by decreasing MMP-2 and MMP-9 secretions via p38 and Akt signaling pathways. Food Chem Toxicol. 2013;59:801–807. doi: 10.1016/j.fct.2013.06.028. PubMed DOI

Zhang Y, Wang S, Liu Z, Yang L, Liu J, Xiu M. Increased Six1 expression in macrophages promotes hepatocellular carcinoma growth and invasion by regulating MMP-9. J Cell Mol Med. 2019;23(7):4523–4533. doi: 10.1111/jcmm.14342. PubMed DOI PMC

Yuan J, Xu XJ, Lin Y, Chen QY, Sun WJ, Tang L, Liang QX. LncRNA MALAT1 expression inhibition suppresses tongue squamous cell carcinoma proliferation, migration and invasion by inactivating PI3K/Akt pathway and downregulating MMP-9 expression. Eur Rev Med Pharmacol Sci. 2019;23(1):198–206. PubMed

Dong H, Diao H, Zhao Y, Xu H, Pei S, Gao J, Wang J, Hussain T, Zhao D, Zhou X. Overexpression of matrix metalloproteinase-9 in breast cancer cell lines remarkably increases the cell malignancy largely via activation of transforming growth factor beta/SMAD signalling. Cell Prolif. 2019;52(5):e12633. doi: 10.1111/cpr.12633. PubMed DOI PMC

Yang HL, Thiyagarajan V, Shen PC, Mathew DC, Lin KY, Liao JW, Hseu YC. Anti-EMT properties of CoQ0 attributed to PI3K/AKT/NFKB/MMP-9 signaling pathway through ROS-mediated apoptosis. J Exp Clin Cancer Res. 2019;38(1):186. doi: 10.1186/s13046-019-1196-x. PubMed DOI PMC

Zhang J, He Z, Wang H, Xu J. A Discussion of the Necessity of Constructing Tourism Service Standards to Cope with Altitude Sickness in the High-Altitude Cold Area. 2021 International Conference on Culture-oriented Science & Technology (ICCST); 2021; IEEE; pp. 580–584. DOI

Xing Q, Parvizi M, Higuita ML, Griffiths LG. Basement membrane proteins modulate cell migration on bovine pericardium extracellular matrix scaffold. Scientific reports. 2021;11(1):1–10. doi: 10.1038/s41598-021-84161-5. PubMed DOI PMC

Roy S, Kim D. Retinal capillary basement membrane thickening: Role in the pathogenesis of diabetic retinopathy. Progress Retinal Eye Res. 2021;82:100903. doi: 10.1016/j.preteyeres.2020.100903. PubMed DOI PMC

Quinlan C, Rheault MN. Genetic basis of type IV collagen disorders of the kidney. Clinical Journal of the American Society of Nephrology. 2021 doi: 10.2215/CJN.19171220. PubMed DOI PMC

Donner I, Sipilä LJ, Plaketti R-M, Kuosmanen A, Forsström L, Katainen R, Kuismin O, Aavikko M, Romsi P, Kariniemi J. Next-generation sequencing in a large pedigree segregating visceral artery aneurysms suggests potential role of COL4A1/COL4A2 in disease etiology. Vascular. 2021:17085381211033157. doi: 10.1177/17085381211033157. PubMed DOI

Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, Bousser MG, Heutink P, Miner JH, Tournier-Lasserve E. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. N Engl J Med. 2006;354(14):1489–1496. doi: 10.1056/NEJMoa053727. PubMed DOI

Schöller K, Trinkl A, Klopotowski M, Thal SC, Plesnila N, Trabold R, Hamann GF, Schmid-Elsaesser R, Zausinger S. Characterization of microvascular basal lamina damage and blood-brain barrier dysfunction following subarachnoid hemorrhage in rats. Brain Res. 2007;1142:237–246. doi: 10.1016/j.brainres.2007.01.034. PubMed DOI

Zhu M, Yang M, Yang Q, Liu W, Geng H, Pan L, Wang L, Ge R, Ji L, Cui S. Chronic Hypoxia-Induced Microvessel Proliferation and Basal Membrane Degradation in the Bone Marrow of Rats Regulated through the IL-6/JAK2/STAT3/MMP-9 Pathway. Biomed Res Int. 2020;2020:9204708. doi: 10.1155/2020/9204708. PubMed DOI PMC

Kumari P, Roy K, Wadhwa M, Chauhan G, Alam S, Kishore K, Ray K, Panjwani U. Fear memory is impaired in hypobaric hypoxia: Role of synaptic plasticity and neuro-modulators in limbic region. Life Sci. 2020;254:117555. doi: 10.1016/j.lfs.2020.117555. PubMed DOI

Shaw S, Kumar U, Bhaumik G, Reddy MPK, Kumar B, Ghosh D. Alterations of estrous cycle, 3β hydroxysteroid dehydrogenase activity and progesterone synthesis in female rats after exposure to hypobaric hypoxia. Sci Rep. 2020;10(1):3458. doi: 10.1038/s41598-020-60201-4. PubMed DOI PMC

Khanna K, Mishra KP, Chanda S, Eslavath MR, Ganju L, Kumar B, Singh SB. Effects of Acute Exposure to Hypobaric Hypoxia on Mucosal Barrier Injury and the Gastrointestinal Immune Axis in Rats. High Alt Med Biol. 2019;20(1):35–44. doi: 10.1089/ham.2018.0031. PubMed DOI

Zimna A, Kurpisz M. Hypoxia-Inducible Factor-1 in Physiological and Pathophysiological Angiogenesis: Applications and Therapies. Biomed Res Int. 2015;2015:549412. doi: 10.1155/2015/549412. PubMed DOI PMC

Fidler AL, Vanacore RM, Chetyrkin SV, Pedchenko VK, Bhave G, Yin VP, Stothers CL, Rose KL, McDonald WH, Clark TA. A unique covalent bond in basement membrane is a primordial innovation for tissue evolution. Proc Natl Acad Sci U S A. 2014;111(1):331–336. doi: 10.1073/pnas.1318499111. PubMed DOI PMC

Shah A, Matsumura N, Quon A, Morton JS, Dyck JRB, Davidge ST. Cardiovascular susceptibility to in vivo ischemic myocardial injury in male and female rat offspring exposed to prenatal hypoxia. Clin Sci (Lond) 2017;131(17):2303–2317. doi: 10.1042/CS20171122. PubMed DOI

Konradi J, Mollenhauer M, Baldus S, Klinke A. Redox-sensitive mechanisms underlying vascular dysfunction in heart failure. Free Radic Res. 2015;49(6):721–742. doi: 10.3109/10715762.2015.1027200. PubMed DOI

Steffensen LB, Stubbe J, Lindholt J, Beck H, Overgaard M, Bloksgaard M, Genovese F, Nielsen SH, Tha M, Bang-Moeller S. Basement membrane collagen IV deficiency promotes abdominal aortic aneurysm formation. Sci Rep. 2021;11(1):1–13. doi: 10.1038/s41598-021-92303-y. PubMed DOI PMC

Niland S, Riscanevo AX, Eble JA. Matrix Metalloproteinases Shape the Tumor Microenvironment in Cancer Progression. Int J Mol Sci. 2022;23(1):146. doi: 10.3390/ijms23010146. PubMed DOI PMC

Mondal S, Adhikari N, Banerjee S, Amin SA, Jha T. Matrix metalloproteinase-9 (MMP-9) and its inhibitors in cancer: A minireview. Eur J Med Chem. 2020;194:112260. doi: 10.1016/j.ejmech.2020.112260. PubMed DOI

Sugiyama A, Okada M, Otani K, Yamawaki H. [Development of basic research toward clinical application of cleaved fragment of type IV collagen]. Nihon Yakurigaku Zasshi. 2021;156(5):282–287. doi: 10.1254/fpj.21016. PubMed DOI

Gomatou G, Syrigos N, Vathiotis IA, Kotteas EA. Tumor Dormancy: Implications for Invasion and Metastasis. Int J Mol Sci. 2021;22(9):4862. doi: 10.3390/ijms22094862. PubMed DOI PMC

Saleh M, Khalil M, Abdellateif MS, Ebeid E, Madney Y, Kandeel EZ. Role of matrix metalloproteinase MMP-2, MMP-9 and tissue inhibitor of metalloproteinase (TIMP-1) in the clinical progression of pediatric acute lymphoblastic leukemia. Hematology. 2021;26(1):758–768. doi: 10.1080/16078454.2021.1978763. PubMed DOI

Verma D, Zanetti C, Godavarthy PS, Kumar R, Minciacchi VR, Pfeiffer J, Metzler M, Lefort S, Maguer-Satta V, Nicolini FE. Bone marrow niche-derived extracellular matrix-degrading enzymes influence the progression of B-cell acute lymphoblastic leukemia. Leukemia. 2020;34(6):1540–1552. doi: 10.1038/s41375-019-0674-7. PubMed DOI PMC