Collagenases MMP-1, MMP-13, and Tissue Inhibitors TIMP-1, TIMP-2: Their Role in Healthy and Complicated Pregnancy and Potential as Preeclampsia Biomarkers—A Brief Review
Abstract
:1. Collagen Type I Characteristics
2. Collagen Type III Characteristics
3. General Features of Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of MMP (TIMPs)
4. Matrix Metalloproteinases and Tissue Inhibitors of MMPs in Preeclampsia
4.1. MMP-1 Structure and Function
4.2. MMP-13 Structure and Function
4.3. TIMP-1 Structure and Function
4.4. TIMP-2 Structure and Function
5. Collagen Type I and III Turnover in Normal Pregnancy
6. Impaired Collagen Type I and III Turnover in Preeclampsia—The Role of MMP/TIMP Complex Dysregulation
6.1. MMP-1 Dysregulation
6.2. MMP-13 Dysregulation
6.3. TIMP-1 and TIMP-2 Dysregulation
7. Conclusions
8. Future Directions
Author Contributions
Funding
Conflicts of Interest
References
- Henriksen, K.; Karsdal, M.A. Type I Collagen. In Biochemistry of Collagens, Laminins and Elastin Structure, Function and Biomarkers, 1st ed.; Karsdal, M.A., Ed.; Academic Press: Cambridge, MA, USA, 2016; Chapter 1; pp. 1–11. [Google Scholar]
- Fleischmajer, R.; Macdonald, E.D.; Perlish, J.S.; Burgeson, R.E.; Fisher, L.W. Dermal collagen fibrils are hybrids of type I and type III collagen molecules. J. Struct. Biol. 1990, 105, 162–169. [Google Scholar] [CrossRef]
- Niyibizi, C.; Eyre, D.R. Bone type V collagen: Chain composition and location of a trypsin cleavage site. Connect. Tissue Res. 1989, 20, 247–250. [Google Scholar] [CrossRef] [PubMed]
- Gelse, K. Collagens—Structure, function, and biosynthesis. Adv. Drug Deliv. Rev. 2003, 55, 1531–1546. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Prockop, D.J.; Kivirikko, K.I. Collagens: Molecular biology, diseases, and potentials for therapy. Annu. Rev. Biochem. 1995, 64, 403–434. [Google Scholar] [CrossRef] [PubMed]
- Fitzgerald, J.; Bateman, J.F. A new FACIT of the collagen family: COL21A. FEBS Lett. 2001, 505, 275–280. [Google Scholar] [CrossRef] [Green Version]
- Rossert, J.; Decrombrugghe, B. Type I collagen structure, synthesis, and regulation. In Principles of Bone Biology; Bilezkian, J., Raisz, J.P., Rodan, L.G., Eds.; Elsevier BV: Amsterdam, The Netherlands, 2002; Volume 1, pp. 189–210. [Google Scholar]
- Von Der Mark, K. Localization of collagen types in tissues. Int. Rev. Connect. Tissue Res. 1981, 9, 265–324. [Google Scholar] [CrossRef] [PubMed]
- Nagase, H.; Visse, R.; Murphy, G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc. Res. 2006, 69, 562–573. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Spinale, F.G. Matrix metalloproteinases: Regulation and dysregulation in the failing heart. Circ. Res. 2002, 90, 520–530. [Google Scholar] [CrossRef] [Green Version]
- Spinale, F.G. Myocardial Matrix remodeling and the Matrix metalloproteinases: Influence on cardiac form and function. Physiol. Rev. 2007, 87, 1285–1342. [Google Scholar] [CrossRef]
- Visse, R.; Nagase, H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: Structure, function, and biochemistry. Circ. Res. 2003, 92, 827–839. [Google Scholar] [CrossRef] [Green Version]
- Woessner, J.F.; Nagase, H. Matrix Metalloproteinases and TIMPs: Protein Profile; Oxford Univ. Press: Oxford, UK, 2000; pp. 8–13. [Google Scholar]
- Gross, J.; Lapiere, C.M. Collagenolytic activity in amphibian tissues: A tissue culture assay. Proc. Natl. Acad. Sci. USA 1962, 48, 1014–1022. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ma, Y.; Padmanahan Iyer, R.; de Castro Brás, L.E.; Toba, H.; Yabluchanskiy, A. Cross talk between inflammation and extracellular matrix following myocardial infarction. In Inflammation in Heart Failure; Academic Press: Cambridge, MA, USA, 2015; Chapter 4; pp. 67–79. [Google Scholar]
- Itoh, Y.; Seiki, M. MT1-MMP: A potent modifier of pericellular microenvironment. J. Cell. Physiol. 2006, 206, 1–8. [Google Scholar] [CrossRef] [PubMed]
- Nagase, H.; Murphy, G. Matrix metalloproteinases. In Encyclopedia of Biological Chemistry, 2nd ed.; Academic Press: Cambridge, MA, USA, 2013; pp. 90–97. [Google Scholar]
- Brew, K.; Nagase, H. The tissue inhibitors of metalloproteinases (TIMPs): An ancient family with structural and functional diversity. Biochim. Biophys. Acta (BBA) Bioenerg. Mol. Cell Res. 2010, 1803, 55–71. [Google Scholar] [CrossRef] [Green Version]
- Kim, Y.-S.; Kim, S.-H.; Kang, J.-G.; Ko, J.-H. Expression level and glycan dynamics determine the net effects of TIMP-1 on cancer progression. BMB Rep. 2012, 45, 623–628. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Creemers, E.E.; Cleutjens, J.P.; Smits, J.F.; Daemen, M.J. Matrix metalloproteinase inhibition after myocardial infarction, a new approach to prevent heart failure? Circ. Res. 2001, 389, 201–210. [Google Scholar] [CrossRef] [Green Version]
- Morgunova, E.; Tuuttila, A.; Bergmann, U.; Tryggvason, K. Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase. Proc. Natl. Acad. Sci. USA 2002, 99, 7414–7419. [Google Scholar] [CrossRef] [Green Version]
- Bourboulia, D.; Stetler-Stevenson, W.G. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion. Semin. Cancer Biol. 2010, 20, 161–168. [Google Scholar] [CrossRef] [Green Version]
- Amaral, L.M.; Wallace, K.; Owens, M.; Lamarca, B. Pathophysiology and current clinical management of preeclampsia. Curr. Hypertens. Rep. 2017, 19, 61. [Google Scholar] [CrossRef] [Green Version]
- Poon, L.C.; Nicolaides, K.H. Early prediction of preeclampsia. Obstet. Gynecol. Int. 2014, 2014, 1–11. [Google Scholar] [CrossRef] [Green Version]
- Pulkkinen, M.; Lehto, M.; Jalkanen, M.; Näntö-Salonen, K. Collagen types and fibronectin in the uterine muscle of normal and hypertensive pregnant patients. Am. J. Obstet. Gynecol. 1984, 149, 711–717. [Google Scholar] [CrossRef]
- Sahay, A.S.; Sundrani, D.P.; Joshi, S.R. Regional changes of placental vascularization in preeclampsia: A review. IUBMB Life 2015, 67, 619–625. [Google Scholar] [CrossRef] [PubMed]
- Wallis, R.M.; Hillier, K. Regulation of collagen dissolution in the human cervix by oestradiol-17 beta and progesterone. J. Reprod. Fertil. 1981, 62, 55–61. [Google Scholar] [CrossRef] [Green Version]
- Sato, T.; Ito, A.; Mori, Y.; Yamashita, K.; Hayakawa, T.; Nagase, H. Hormonal regulation of collagenolysis in uterine cervical fibroblasts. Modulation of synthesis of procollagenase, prostromelysin and tissue inhibitor of metalloproteinases (TIMP) by progesterone and oestradiol-17 beta. Biochem. J. 1991, 275, 645–650. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Uldbjerg, N.; Forman, A.; Petersen, L. Biochemical changes of the uterus and cervix during pregnancy. In Medicine of the Fetus and Mother; Reece, E.A., Hobbins, J.C., Mahoney, M.J., Petrie, R.H., Eds.; JB Lippincott Co.: Philadelphia, PA, USA, 1992; pp. 849–868. [Google Scholar]
- Burrows, T.D.; King, A.; Lok, Y.W. European society for human reproduction and embryology trophoblast migration during human placental implantation. Hum. Reprod. Update 1996, 2, 307–321. [Google Scholar] [CrossRef] [Green Version]
- Zhou, Y.; Damsky, C.H.; Chiu, K.; Roberts, J.M.; Fisher, S.J. Preeclampsia is associated with abnormal expression of adhesion molecules by invasive cytotrophoblasts. J. Clin. Investig. 1993, 91, 950–960. [Google Scholar] [CrossRef] [Green Version]
- Goldman-Wohl, D.S.; Yagel, S. Examination of distinct fetal and maternal molecular pathways suggests a mechanism for the development of preeclampsia. J. Reprod. Immunol. 2007, 76, 54–60. [Google Scholar] [CrossRef]
- Goldman-Wohl, D.; Yagel, S. Regulation of trophoblast invasion: From normal implantation to pre-eclampsia. Mol. Cell. Endocrinol. 2002, 187, 233–238. [Google Scholar] [CrossRef]
- Merchant, S.J.; Davidge, S.T. The role of matrix metalloproteinases in vascular function: Implications for normal pregnancy and pre-eclampsia. BJOG Int. J. Obstet. Gynaecol. 2004, 111, 931–939. [Google Scholar] [CrossRef]
- Danforth, D. The fibrous nature of the human cervix, and its relation to the isthmic segment in gravid and nongravid uteri. Am. J. Obstet. Gynecol. 1947, 53, 541–560. [Google Scholar] [CrossRef]
- Kitamura, K.; Ito, A.; Mori, Y.; Hirakawa, S. Glycosaminoglycans of human uterine cervix: Heparan sulfate increase with reference to cervical ripening. Biochem. Med. 1980, 23, 159–166. [Google Scholar] [CrossRef]
- Harmon, A.C.; Cornelius, D.C.; Amaral, L.M.; Faulkner, J.L.; Cunningham, M.W., Jr.; Wallace, K.; LaMarca, B. The role of inflammation in the pathology of preeclampsia. Clin. Sci. (Lond.) 2016, 130, 409–419. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- American College of Obstetricians and Gynecologists. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ task force on hypertension in pregnancy. Obstet. Gynecol. 2013, 122, 1122–1130. [Google Scholar]
- Eiland, E.; Nzerue, C.; Faulkner, M. Preeclampsia 2012. J. Pregnancy 2012, 2012, 1–7. [Google Scholar] [CrossRef] [Green Version]
- Pulkkinen, M.O.; Kivikoski, A.I.; Nevalainen, T.J. Group I and group II phospholipase A2 in serum during normal and pathological pregnancy. Gynecol. Obstet. Invest. 1993, 36, 96–101. [Google Scholar] [CrossRef]
- Henriksen, K.; Karsdal, M.A. Type I Collagen. In Biochemistry of Collagens, Laminins and Elastin Structure, Function and Biomarkers, 2nd ed.; Karsdal, M.A., Ed.; Elsevier: Amsterdam, The Netherlands, 2019; Chapter 1; pp. 1–12. [Google Scholar]
- Nielsen, M.J.; Karsdal, M.A. Type III Collagen. In Biochemistry of Collagens, Laminins and Elastin Structure, Function and Biomarkers, 2nd ed.; Academic Press: Cambridge, MA, USA, 2019; Chapter 3; pp. 21–30. [Google Scholar]
- Shi, J.-W.; Lai, Z.-Z.; Yang, H.-L.; Yang, S.-L.; Wang, C.-J.; Ao, D.; Ruan, L.-Y.; Shen, H.-H.; Zhou, W.-J.; Mei, J.; et al. Collagen at the maternal-fetal interface in human pregnancy. Int. J. Biol. Sci. 2020, 16, 2220–2234. [Google Scholar] [CrossRef]
- Lim, K.H.; Zhou, Y.; Janatpour, M.; McMaster, M.; Bass, K.; Chun, S.H.; Fisher, S.J. Human cytotrophoblast differentiation/invasion is abnormal in pre-eclampsia. Am. J. Pathol. 1997, 151, 1809–1818. [Google Scholar]
- Karthikeyan, V.J.; A Lane, D.; Beevers, D.G.; Lip, G.Y.H.; Blann, A.D. Matrix metalloproteinases and their tissue inhibitors in hypertension-related pregnancy complications. J. Hum. Hypertens. 2012, 27, 72–78. [Google Scholar] [CrossRef] [Green Version]
- Wang, Z.; Lu, S.; Liu, C.; Zhao, B.; Pei, K.; Tian, L.; Ma, X. Expressional and epigenetic alterations of placental matrix metalloproteinase 9 in preeclampsia. Gynecol. Endocrinol. 2010, 26, 96–102. [Google Scholar] [CrossRef]
- Merchant, S.J.; Narumiya, H.; Zhang, Y.; Guilbert, L.J.; Davidge, S.T. The effects of preeclampsia and oxygen environment on endothelial release of matrix metalloproteinase. Hypertens. Pregnancy 2004, 23, 47–60. [Google Scholar] [CrossRef] [PubMed]
- Galewska, Z.; Bańkowski, E.; Romanowicz, L.; Jaworski, S. Pre-eclampsia (EPH-gestosis)-induced decrease of MMP-s content in the umbilical cord artery. Clin. Chim. Acta 2003, 335, 109–115. [Google Scholar] [CrossRef]
- Narumiya, H.; Zhang, Y.; Fernandez-Patron, C.; Guilbert, L.J.; Davidge, S.T. Matrix metalloproteinase-2 is elevated in the plasma of women with preeclampsia. Hypertens. Pregnancy 2001, 20, 185–194. [Google Scholar] [CrossRef] [PubMed]
- Mahameed, S.; Goldman, S.; Gabarin, D.; Weiss, A.; Shalev, E. The effect of serum from women with preeclampsia on JAR (trophoblast-like) cell line. J. Soc. Gynecol. Investig. 2005, 12, e45–e50. [Google Scholar] [CrossRef] [PubMed]
- Lian, I.A.; Toft, J.H.; Olsen, G.D. Matrix metalloproteinase 1 in pre-eclampsia and fetal growth restriction: Reduced gene expression in decidual tissue and protein expression in extravillous trophoblasts. Placenta 2010, 31, 615–620. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nakano, M.; Hara, T.; Hayama, T.; Obara, M.; Yoshizato, K.; Ohama, K. Membrane-type 1 matrix metalloproteinase is induced in decidual stroma without direct invasion by trophoblasts. Mol. Hum. Reprod. 2001, 7, 271–277. [Google Scholar] [CrossRef] [Green Version]
- Hurskainen, T.; Seiki, M.; Apte, S.S.; Syrjäkallio–Ylitalo, M.; Sorsa, T.; Oikarinen, A.; Autio–Harmainen, H. Production of membrane-type matrix metalloproteinase-1 (MT-MMP-1) in early human placenta: A possible role in placental implantation? J. Histochem. Cytochem. 1998, 46, 221–229. [Google Scholar] [CrossRef]
- Lian, I.A.; Løset, M.; Mundal, S.B.; Fenstad, M.H.; Johnson, M.P.; Eide, I.P.; Bjørge, L.; Freed, K.A.; Moses, E.K.; Austgulen, R. Increased endoplasmic reticulum stress in decidual tissue from pregnancies complicated by fetal growth restriction with and without pre-eclampsia. Placenta 2011, 32, 823–829. [Google Scholar] [CrossRef] [Green Version]
- Raffetto, J.D.; Khalil, R.A. Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochem. Pharmacol. 2008, 75, 346–359. [Google Scholar] [CrossRef] [Green Version]
- Estrada-Gutierrez, G.; Cappello, R.; Mishra, N.; Romero, R.; Strauss, J.; Walsh, S. Increased Expression of Matrix Metalloproteinase-1 in Systemic Vessels of Preeclamptic Women A Critical Mediator of Vascular Dysfunction. Am. J. Pathol. 2011, 178, 451–459. [Google Scholar] [CrossRef]
- Gupta, M.; Chari, S. Assessment of matrix metalloproteinase-1 and its tissue inhibitor of metalloproteinase-1 in pre-eclampsia. Int. J. Sci. Study 2016, 3, 70–73. [Google Scholar]
- Li, W.; Cui, N.; Mazzuca, M.Q.; Mata, K.M.; Khalil, R.A. Increased vascular and uteroplacental matrix metalloproteinase-1 and-7 levels and collagen type I deposition in hypertension in pregnancy: Role of TNF-α. Am. J. Physiol. Heart Circ. Physiol. 2017, 313, H491–H507. [Google Scholar] [CrossRef]
- Deng, C.-L.; Ling, S.-T.; Liu, X.-Q.; Zhao, Y.-J.; Lv, Y.-F. Decreased expression of matrix metalloproteinase-1 in the maternal umbilical serum, trophoblasts and decidua leads to preeclampsia. Exp. Ther. Med. 2015, 9, 992–998. [Google Scholar] [CrossRef] [PubMed]
- Laskowska, M. Altered maternal serum matrix metalloproteinases MMP-2, MMP-3, MMP-9, and MMP-13 in severe early-and late-onset preeclampsia. BioMed Res. Int. 2017, 2017, 1–9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Luizon, M.R.; Palei, A.C.T.; Sandrim, V.C.; Amaral, L.M.; Machado, J.S.R.; Lacchini, R. Tissue inhibitor of metalloproteinase (TIMP)-1 is a major endogenous inhibitor of matrix metalloproteinase (MMP)-9, which may affect the responsiveness to therapy in hypertensive disorders of pregnancy. Pharmacogenom. J. 2014, 14, 535–541. [Google Scholar] [CrossRef] [PubMed]
- Tayebjee, M.; Karalis, I.; Nadar, S.; Beevers, D.J.; MacFadyen, R.; Lip, G.Y.H. Circulating matrix metalloproteinase–9 and tissue inhibitors of metalloproteinases–1 and –2 levels in gestational hypertension. AJH 2005, 18, 325–329. [Google Scholar] [CrossRef]
- Myers, J.E.; Merchant, S.J.; MacLeod, M.; Mires, G.J.; Baker, P.N.; Davidge, S.T. MMP-2 levels are elevated in the plasma of women who subsequently develop preeclampsia. Hypertens. Pregnancy 2005, 24, 103–115. [Google Scholar] [CrossRef] [PubMed]
- Palei, A.C.; Sandrim, V.C.; Cavalli, R.D.C.; Tanus-Santos, J.E. Comparative assessment of matrix metalloproteinase (MMP)-2 and MMP-9, and their inhibitors, tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 in preeclampsia and gestational hypertension. Clin. Biochem. 2008, 41, 875–880. [Google Scholar] [CrossRef] [PubMed]
- Palei, A.C.; Sandrim, V.C.; Amaral, L.M.; Machado, J.S.R.; Cavalli, R.D.C.; Duarte, G.; Tanus-Santos, J.E. Association between matrix metalloproteinase (MMP)-2 polymorphisms and MMP-2 levels in hypertensive disorders of pregnancy. Exp. Mol. Pathol. 2012, 92, 217–221. [Google Scholar] [CrossRef]
- Ab Hamid, J.; Mohtarrudin, N.; Osman, M.; Asri, A.A.; Hassan, W.H.W.; Aziz, R. Matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases 1 and 2 as potential biomarkers for gestational hypertension. Singap. Med. J. 2012, 53, 681–683. [Google Scholar]
- Kenny, L.C.; Black, M.A.; Poston, L.; Taylor, R.; Myers, J.E.; Baker, P.N.; McCowan, L.M.; Simpson, N.A.B.; Dekker, G.A.; Roberts, C.T.; et al. Early pregnancy prediction of preeclampsia in nulliparous women, combining clinical risk and biomarkers the screening for pregnancy endpoints (SCOPE) international cohort study. Hypertension 2014, 64, 644–652. [Google Scholar] [CrossRef] [Green Version]
- Montagnana, M.; Lippi, G.; Albiero, A.; Scevarolli, S.; Salvagno, G.L.; Franchi, M.; Guidi, G.C. Evaluation of metalloproteinases 2 and 9 and their inhibitors in physiologic and pre-eclamptic pregnancy. J. Clin. Lab. Anal. 2009, 23, 88–92. [Google Scholar] [CrossRef]
Authors | Hypertensive Disorders of Pregnancy Type | Sample Type | Method | Main Findings |
---|---|---|---|---|
Guadalupe et al. [56] | PE | Plasma | Zymograph ELISA | Increased expression in systemic vessels Increased MMP-1 levels |
Gupta et al. [57] | PE | Serum | ELISA | Non significant difference in 2nd-3rd trimester |
W. Li et al. [58] | PE | Aorta, uterus, placenta | Zymography | Increased MMP-1 expression in aorta, uterus and placenta of rats |
Chun Lei et al. [59] | PE | Maternal umbilical serum | ELISA | Decreased MMP-1 levels |
Authors | Hypertensive Disorders of Pregnancy Type | Sample Type | Method | Main Findings |
---|---|---|---|---|
Luizon et al. [61] | PE, GH | Plasma | ELISA | Increased TIMP-1 levels in PE patients with TG-genotype GH patients with GG-genotype had lower MMP-9/TIMP-1 ratios than those with TT-genotype |
Gupta et al. [57] | PE | Serum | ELISA | Non significant difference in 2nd-3rd trimester Non-significant MMP-1/TIMP-1 ratio |
Tayebjee et al. [62] | GH | Plasma | ELISA | Increased TIMP-1 levels |
Myers Jenny et al. [63] | PE | Plasma | Zymography | Decreased TIMP-1 activity at 22 and 26 weeks Imbalanced MMP-2/TIMP-1 ratio |
Ab Hamid et al. [66] | GH | Serum | ELISA | Decreased TIMP-1 levels |
Montegrana et al. [68] | PE | Serum | ELISA | Increased TIMP-1 levels |
Palei et al. [64] | PE, GH | Plasma | Zymography ELISA | Increased TIMP-1 levels |
SCOPE [67] | PE | Plasma | Increased TIMP-1 levels |
Authors | Hypertensive Disorders of Pregnancy Type | Sample Type | Method | Main Findings |
---|---|---|---|---|
Palei et al. [64] | PE, GH | Plasma | Zymography ELISA | Increased TIMP-2 levels |
Tayebjee et al. [62] | GH | Plasma | ELISA | Increased TIMP-2 levels |
Myers Jenny et al. [63] | PE | Plasma | Zymography | Non significant difference TIMP-2 activity at 22 and 26 weeks |
Ab Hamid et al. [66] | GH | Serum | ELISA | Decreased TIMP-2 levels |
Montegrana et al. [68] | PE | Serum | ELISA | Increased TIMP-2 levels |
Palei et al. [65] | PE, GH | Plasma | ELISA | Increased TIMP-2 levels in PE Increased MMP-2/TIMP-2 ratio in GH |
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Nikolov, A.; Popovski, N.; Hristova, I. Collagenases MMP-1, MMP-13, and Tissue Inhibitors TIMP-1, TIMP-2: Their Role in Healthy and Complicated Pregnancy and Potential as Preeclampsia Biomarkers—A Brief Review. Appl. Sci. 2020, 10, 7731. https://doi.org/10.3390/app10217731
Nikolov A, Popovski N, Hristova I. Collagenases MMP-1, MMP-13, and Tissue Inhibitors TIMP-1, TIMP-2: Their Role in Healthy and Complicated Pregnancy and Potential as Preeclampsia Biomarkers—A Brief Review. Applied Sciences. 2020; 10(21):7731. https://doi.org/10.3390/app10217731
Chicago/Turabian StyleNikolov, Asparuh, Nikola Popovski, and Irena Hristova. 2020. "Collagenases MMP-1, MMP-13, and Tissue Inhibitors TIMP-1, TIMP-2: Their Role in Healthy and Complicated Pregnancy and Potential as Preeclampsia Biomarkers—A Brief Review" Applied Sciences 10, no. 21: 7731. https://doi.org/10.3390/app10217731
APA StyleNikolov, A., Popovski, N., & Hristova, I. (2020). Collagenases MMP-1, MMP-13, and Tissue Inhibitors TIMP-1, TIMP-2: Their Role in Healthy and Complicated Pregnancy and Potential as Preeclampsia Biomarkers—A Brief Review. Applied Sciences, 10(21), 7731. https://doi.org/10.3390/app10217731