Updating the role of matrix metalloproteinases in mineralized tissue and related diseases

Bone development and healing processes involve a complex cascade of biological events requiring well-orchestrated synergism with bone cells, growth factors, and other trophic signaling molecules and cellular structures. Beyond health processes, MMPs play several key roles in the installation of heart and blood vessel related diseases and cancer, ranging from accelerating metastatic cells to ectopic vascular mineralization by smooth muscle cells in complementary manner. The tissue inhibitors of MMPs (TIMPs) have an important role in controlling proteolysis. Paired with the post-transcriptional efficiency of specific miRNAs, they modulate MMP performance. If druggable, these molecules are suggested to be a platform for development of “smart” medications and further clinical trials. Thus, considering the pleiotropic effect of MMPs on mammals, the purpose of this review is to update the role of those multifaceted proteases in mineralized tissues in health, such as bone, and pathophysiological disorders, such as ectopic vascular calcification and cancer.

Keywords:
Extracellular matrix; Matrix metalloproteinases; Bone; Vascular calcification; Extracellular vesicles

Authorship

Cintia Kazuko Tokuhara

Universidade de São Paulo, Faculdade de Odontologia de Bauru, Departamento de Ciências Biológicas, Laboratório de Bioquímica, Bauru, São Paulo, BrasilUniversidade de São PauloBrasilBauru, São Paulo, BrasilUniversidade de São Paulo, Faculdade de Odontologia de Bauru, Departamento de Ciências Biológicas, Laboratório de Bioquímica, Bauru, São Paulo, Brasil

https://orcid.org/0000-0002-1852-5986

Mariana Rodrigues Santesso

https://orcid.org/0000-0001-9740-1780

Gabriela Silva Neubern de Oliveira

https://orcid.org/0000-0003-0037-5665

Talita Mendes da Silva Ventura

https://orcid.org/0000-0003-2101-1350

Julio Toshimi Doyama

Universidade Estadual Paulista Júlio de Mesquita Filho, Campus Botucatu, Rubião Jr, São Paulo, BrasilUniversidade Estadual Paulista Júlio de Mesquita FilhoBrasilSão Paulo, BrasilUniversidade Estadual Paulista Júlio de Mesquita Filho, Campus Botucatu, Rubião Jr, São Paulo, Brasil

https://orcid.org/0000-0001-9456-4111

Willian Fernando Zambuzzi

https://orcid.org/0000-0002-4149-5965

Rodrigo Cardoso de Oliveira Corresponding address: Rodrigo Cardoso de Oliveira, Departmento de Ciências Biológicas - Faculdade de Odontologia de Bauru - Universidade de São Paulo. Al. Octávio Pinheiro Brisolla, 9-75 - Bauru - SP - 17012-901 - Brasil. Phone: + 55 14 32358321 e-mail: rodrigocardoso@usp.br

https://orcid.org/0000-0003-3070-5960

Corresponding address: Rodrigo Cardoso de Oliveira, Departmento de Ciências Biológicas - Faculdade de Odontologia de Bauru - Universidade de São Paulo. Al. Octávio Pinheiro Brisolla, 9-75 - Bauru - SP - 17012-901 - Brasil. Phone: + 55 14 32358321 e-mail: rodrigocardoso@usp.br

Conflicts of interest

The authors declare that they have no conflict of interest.

SCIMAGO INSTITUTIONS RANKINGS

Figures

Figures (5)

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Figure 1
List of major MMPs involved in bone repair processes and their tissue inhibitors (TIMP)⁹9- Radomski A, Jurasz P, Sanders EJ, Overall CM, Bigg HF, Edwards DR, et al. Identification, regulation and role of tissue inhibitor of metalloproteinases-4 (TIMP-4) in human platelets. Br J Pharmacol. 2002;137(8):1330-8.^–¹⁵15- Itoh Y. Membrane-type matrix metalloproteinases: their functions and regulations. Matrix Biol. 2015;44-46:207-23.

Thumbnail

Figure 2
List of MMPs, according their classification and substrate¹⁸18- Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92(8):827-39.^,²⁹29- Bonnans C, Chou J, Werb Z. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol. 2014;15(12):786-801.

Thumbnail

Figure 3
Matrix metalloproteinases are involved in several biological mechanisms, mainly in bone repair and regeneration, which occurs during the homeostasis of MMPs when the osteoclast performs their role in reabsorption and the osteoblast forms a new matrix. In contrast, the MMPs act in pathological conditions such as progression of tumor, bone diseases as OA or RA and ectopic cardiovascular calcification. Pathophysiological conditions have been observed showing that the action of EVs and miRNAs had implicated in the regulation of MMPs acting in others functions in the organism²¹21- Page-McCaw A, Ewald AJ, Werb Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol. 2007;8(3):221-33.^–²³23- Gharagozlian S, Svennevig K, Bangstad HJ, Winberg JO, Kolset SO. Matrix metalloproteinases in subjects with type 1 diabetes. BMC Clin Pathol. 2009;9:7.^,³⁶36- Nawaz M, Shah N, Zanetti BR, Maugeri M, Silvestre RN, Fatima F, et al. Extracellular vesicles and matrix remodeling enzymes: the emerging roles in extracellular matrix remodeling, progression of diseases and tissue repair. Cells. 2018;7(10).^–⁴⁶46- Sapna G, Gokul S, Bagri-Manjrekar K. Matrix metalloproteinases and periodontal diseases. Oral Dis. 2014;20(6):538-50.

Thumbnail

Figure 4
Osteoblast cells release MMPs (as −2, −3, −9 and −13), which have an important role in bone metabolism, activating osteoclast cells and consequently initiating matrix degradation. Afterwards, several matrix metalloproteinases work in coordination in order to form new ECM. Thus, a new mineralized matrix is formed through regulatory mechanism of cells and MMPs⁴4- Mizutani A, Sugiyama I, Kuno E, Matsunaga S, Tsukagoshi N. Expression of matrix metalloproteinases during ascorbate-induced differentiation of osteoblastic MC3T3-E1 cells. J Bone Miner Res. 2001;16(11):2043-9.^,²⁰20- Paiva KB, Granjeiro JM. Matrix metalloproteinases in bone resorption, remodeling, and repair. Prog Mol Biol Transl Sci. 2017;148:203-303.^,²⁴24- Lieu S, Hansen E, Dedini R, Behonick D, Werb Z, Miclau T, et al. Impaired remodeling phase of fracture repair in the absence of matrix metalloproteinase-2. Dis Model Mech. 2011;4(2):203-11.^,⁴⁷47- Accorsi-Mendonça T, Paiva KB, Zambuzzi WF, Cestari TM, Lara VS, Sogayar MC, et al. Expression of matrix metalloproteinases-2 and −9 and RECK during alveolar bone regeneration in rat. J Mol Histol. 2008;39(2):201-8.

Thumbnail

Figure 5
Summary of the miRNAs effect over MMPs in some diseases⁷⁸78- Stanczyk J, Ospelt C, Karouzakis E, Filer A, Raza K, Kolling C, et al. Altered expression of microRNA-203 in rheumatoid arthritis synovial fibroblasts and its role in fibroblast activation. Arthritis Rheum. 2011;63(2):373-81.^–⁹³93- Xiao R, Li C, Chai B. miRNA-144 suppresses proliferation and migration of colorectal cancer cells through GSPT1. Biomed Pharmacother. 2015;74:138-44.

Figure 1 List of major MMPs involved in bone repair processes and their tissue inhibitors (TIMP)⁹9- Radomski A, Jurasz P, Sanders EJ, Overall CM, Bigg HF, Edwards DR, et al. Identification, regulation and role of tissue inhibitor of metalloproteinases-4 (TIMP-4) in human platelets. Br J Pharmacol. 2002;137(8):1330-8.^–¹⁵15- Itoh Y. Membrane-type matrix metalloproteinases: their functions and regulations. Matrix Biol. 2015;44-46:207-23.

Figure 2 List of MMPs, according their classification and substrate¹⁸18- Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92(8):827-39.^,²⁹29- Bonnans C, Chou J, Werb Z. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol. 2014;15(12):786-801.

Figure 3 Matrix metalloproteinases are involved in several biological mechanisms, mainly in bone repair and regeneration, which occurs during the homeostasis of MMPs when the osteoclast performs their role in reabsorption and the osteoblast forms a new matrix. In contrast, the MMPs act in pathological conditions such as progression of tumor, bone diseases as OA or RA and ectopic cardiovascular calcification. Pathophysiological conditions have been observed showing that the action of EVs and miRNAs had implicated in the regulation of MMPs acting in others functions in the organism²¹21- Page-McCaw A, Ewald AJ, Werb Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol. 2007;8(3):221-33.^–²³23- Gharagozlian S, Svennevig K, Bangstad HJ, Winberg JO, Kolset SO. Matrix metalloproteinases in subjects with type 1 diabetes. BMC Clin Pathol. 2009;9:7.^,³⁶36- Nawaz M, Shah N, Zanetti BR, Maugeri M, Silvestre RN, Fatima F, et al. Extracellular vesicles and matrix remodeling enzymes: the emerging roles in extracellular matrix remodeling, progression of diseases and tissue repair. Cells. 2018;7(10).^–⁴⁶46- Sapna G, Gokul S, Bagri-Manjrekar K. Matrix metalloproteinases and periodontal diseases. Oral Dis. 2014;20(6):538-50.

Figure 4 Osteoblast cells release MMPs (as −2, −3, −9 and −13), which have an important role in bone metabolism, activating osteoclast cells and consequently initiating matrix degradation. Afterwards, several matrix metalloproteinases work in coordination in order to form new ECM. Thus, a new mineralized matrix is formed through regulatory mechanism of cells and MMPs⁴4- Mizutani A, Sugiyama I, Kuno E, Matsunaga S, Tsukagoshi N. Expression of matrix metalloproteinases during ascorbate-induced differentiation of osteoblastic MC3T3-E1 cells. J Bone Miner Res. 2001;16(11):2043-9.^,²⁰20- Paiva KB, Granjeiro JM. Matrix metalloproteinases in bone resorption, remodeling, and repair. Prog Mol Biol Transl Sci. 2017;148:203-303.^,²⁴24- Lieu S, Hansen E, Dedini R, Behonick D, Werb Z, Miclau T, et al. Impaired remodeling phase of fracture repair in the absence of matrix metalloproteinase-2. Dis Model Mech. 2011;4(2):203-11.^,⁴⁷47- Accorsi-Mendonça T, Paiva KB, Zambuzzi WF, Cestari TM, Lara VS, Sogayar MC, et al. Expression of matrix metalloproteinases-2 and −9 and RECK during alveolar bone regeneration in rat. J Mol Histol. 2008;39(2):201-8.

Figure 5 Summary of the miRNAs effect over MMPs in some diseases⁷⁸78- Stanczyk J, Ospelt C, Karouzakis E, Filer A, Raza K, Kolling C, et al. Altered expression of microRNA-203 in rheumatoid arthritis synovial fibroblasts and its role in fibroblast activation. Arthritis Rheum. 2011;63(2):373-81.^–⁹³93- Xiao R, Li C, Chai B. miRNA-144 suppresses proliferation and migration of colorectal cancer cells through GSPT1. Biomed Pharmacother. 2015;74:138-44.

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Updating the role of matrix metalloproteinases in mineralized tissue and related diseases

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[1] Corresponding address: Rodrigo Cardoso de Oliveira, Departmento de Ciências Biológicas - Faculdade de Odontologia de Bauru - Universidade de São Paulo. Al. Octávio Pinheiro Brisolla, 9-75 - Bauru - SP - 17012-901 - Brasil. Phone: + 55 14 32358321 e-mail: rodrigocardoso@usp.br