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MMP3
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesMMP3, CHDS6, MMP-3, SL-1, STMY, STMY1, STR1, matrix metallopeptidase 3
External IDsOMIM: 185250; MGI: 97010; HomoloGene: 20545; GeneCards: MMP3; OMA:MMP3 - orthologs
EC number3.4.24.17
Orthologs
SpeciesHumanMouse
Entrez

4314

17392

Ensembl

ENSG00000149968

ENSMUSG00000043613

UniProt

P08254

P28862

RefSeq (mRNA)

NM_002422

NM_010809

RefSeq (protein)

NP_002413

NP_034939

Location (UCSC)Chr 11: 102.84 – 102.84 MbChr 9: 7.45 – 7.46 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Stromelysin 1
Identifiers
EC no.3.4.24.17
CAS no.79955-99-0
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Search
PMCarticles
PubMedarticles
NCBIproteins

Stromelysin-1 also known as matrix metalloproteinase-3 (MMP-3) is an enzyme that in humans is encoded by the MMP3 gene. The MMP3 gene is part of a cluster of MMP genes which localize to chromosome 11q22.3.[5] MMP-3 has an estimated molecular weight of 54 kDa.[6]

Function

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Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix proteins and during tissue remodeling in normal physiological processes, such as embryonic development and reproduction, as well as in disease processes, such as arthritis, and tumour metastasis. Most MMPs are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases.[7]

The MMP-3 enzyme degrades collagen types II, III, IV, IX, and X, proteoglycans, fibronectin, laminin, and elastin.[8][9][10] In addition, MMP-3 can also activate other MMPs such as MMP-1, MMP-7, and MMP-9, rendering MMP-3 crucial in connective tissue remodeling.[11] The enzyme is also thought to be involved in wound repair, progression of atherosclerosis, and tumor initiation.

In addition to classical roles for MMP3 in extracellular space, MMP3 can enter in cellular nuclei and control transcription.[12]

Gene regulation

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MMP3 itself can enter in nuclei of cells and regulate target gene such as CTGF/CCN2 gene.[12]

Expression of MMP3 is primarily regulated at the level of transcription, where the promoter of the gene responds to various stimuli, including growth factors, cytokines, tumor promoters, and oncogene products.[13] A polymorphism in the promoter of the MMP3 gene was first reported in 1995.[14] The polymorphism is caused by a variation in the number of adenosines located at position -1171 relative to the transcription start site, resulting in one allele having five adenosines (5A) and the other allele having six adenosines (6A). In vitro promoter functional analyses showed that the 5A allele had greater promoter activities as compared with the 6A allele.[11] It has been shown in different studies that individuals carrying the 5A allele have increased susceptibility to diseases attributed to increased MMP expression, such as acute myocardial infarction and abdominal aortic aneurysm.[15][16]

On the other hand, the 6A allele has been found to be associated with diseases characterized by insufficient MMP-3 expression due to a lower promoter activity of the 6A allele, such as progressive coronary atherosclerosis.[11][17][18] The -1171 5A/6A variant has also been associated with congenital anomalies such as cleft lip and palate, where individuals with cleft lip/palate presented significantly more 6A/6A genotypes than controls.[19] Recently, the MMP3 gene was shown to be down-regulated in individuals with cleft lip and palate when compared to controls,[20] reinforcing the nature of cleft lip/palate as a condition resulting from insufficient or defective embryonic tissue remodeling.

Structure

[edit]
General structure for matrix metalloproteinases.

Most members of the MMP family are organized into three basic, distinctive, and well-conserved domains based on structural considerations: an amino-terminal propeptide; a catalytic domain; and a hemopexin-like domain at the carboxy-terminal. The propeptide consists of approximately 80–90 amino acids containing a cysteine residue, which interacts with the catalytic zinc atom via its side chain thiol group. A highly conserved sequence (. . .PRCGXPD. . .) is present in the propeptide. Removal of the propeptide by proteolysis results in zymogen activation, as all members of the MMP family are produced in a latent form.

The catalytic domain contains two zinc ions and at least one calcium ion coordinated to various residues. One of the two zinc ions is present in the active site and is involved in the catalytic processes of the MMPs. The second zinc ion (also known as structural zinc) and the calcium ion are present in the catalytic domain approximately 12 Å away from the catalytic zinc. The catalytic zinc ion is essential for the proteolytic activity of MMPs; the three histidine residues that coordinate with the catalytic zinc are conserved among all the MMPs. Little is known about the roles of the second zinc ion and the calcium ion within the catalytic domain, but the MMPs are shown to possess high affinities for structural zinc and calcium ions.

TIMP-1 (blue) in complex with MMP-3 (red). Note the Cys1 (green) TIMP-1 chelating to the catalytic zinc (purple). Calcium ions (yellow) are also shown. Based on the PyMOL rendering of PDB 1UEA. For simplicity, the other MMP-3 monomer complexed with its respective TIMP-1 is not shown.

The catalytic domain of MMP-3 can be inhibited by tissue inhibitors of metalloproteinases (TIMPs). The n-terminal fragment of the TIMP binds in the active site cleft much like the peptide substrate would bind. The Cys1 residue of the TIMP chelates to the catalytic zinc and forms hydrogen bonds with one of the carboxylate oxygens of the catalytic glutamate residue (Glu202, see mechanism below). These interactions force the zinc-bound water molecule that is essential to the enzyme's function to leave the enzyme. The loss of the water molecule and the blocking of the active site by TIMP disable the enzyme.[21]

The hemopexin-like domain of MMPs is highly conserved and shows sequence similarity to the plasma protein, hemopexin. The hemopexin-like domain has been shown to play a functional role in substrate binding and/or in interactions with the tissue inhibitors of metalloproteinases (TIMPs), a family of specific MMP protein inhibitors.[22]

Mechanism

The mechanism for MMP-3 is a variation on a larger theme seen in all matrix metalloproteinases. In the active site, a water molecule is coordinated to a glutamate residue (Glu202) and one of the zinc ions present in the catalytic domain. First, the coordinated water molecule performs a nucleophilic attack on the peptide substrate's scissile carbon while the glutamate simultaneously abstracts a proton from the water molecule. The abstracted proton is then removed from the glutamate by the nitrogen of the scissile amide. This forms a tetrahedral gem-diolate intermediate that is coordinated to the zinc atom.[23] In order for the amide product to be released from the active site, the scissile amide must abstract a second proton from the coordinated water molecule.[24] Alternatively, it has been shown for thermolysin (another metalloproteinase) that the amide product can be released in its neutral (R-NH2) form.[25][26] The carboxylate product is released after a water molecule attacks the zinc ion and displaces the carboxylate product.[27] The release of the carboxylate product is thought to be the rate-limiting step in the reaction.[26]

In addition to the water molecule directly involved in the mechanism, a second water molecule is suggested to be a part of the MMP-3 active site. This auxiliary water molecule is thought to stabilize the gem-diolate intermediate as well as the transition states by lowering the activation energy for their formation.[23][28] This is demonstrated in the mechanism and reaction coordinate diagram below.

The catalytic mechanism for MMP-3 with an auxiliary water molecule. Charges shown are formal charges.

Disease relevance

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MMP-3 has been implicated in exacerbating the effects of traumatic brain injury (TBI) through its disruption of the blood-brain barrier (BBB). Different studies have shown that after the brain undergoes trauma and inflammation has begun, MMP production in the brain is increased.[29][30] In a study conducted using MMP-3 wild type (WT) and knockout (KO) mice, MMP-3 was shown to increase BBB permeability after traumatic injury.[31] The WT mice were shown to have lower claudin-5 and occludin levels than the KO mice after TBI. Claudin and occludin are proteins that are essential for the formation of the tight junctions between the cells of the blood-brain barrier.[32][33] Tissue from uninjured WT and KO mice brains was also treated with active MMP-3. Both the WT and KO tissues showed a drop in claudin-5, occludin, and laminin-α1 (a basal lamina protein), suggesting that MMP-3 directly destroys tight junction and basal lamina proteins.

MMP-3 also does damage to the blood-spinal cord barrier (BSCB), the functional equivalent of the blood-brain barrier,[34] after spinal cord injury (SCI). In a similar study conducted using MMP-3 WT and KO mice, MMP-3 was shown to increase BSCB permeability, with the WT mice showing greater BSCB permeability than the KO mice after spinal cord injury. The same study also found decreased BSCB permeability when spinal cord tissues were treated with a MMP-3 inhibitor. These results suggest that the presence of MMP-3 serves to increase BSCB permeability after SCI.[35] The study showed that MMP-3 accomplishes this damage by degrading claudin-5, occludin, and ZO-1 (another tight junction protein), similar to how MMP-3 damages the BBB.

The increase in blood-brain barrier and blood-spinal cord barrier permeability allows for more neutrophils to infiltrate the brain and spinal cord at the site of inflammation.[31] Neutrophils carry MMP-9.,[36] which has also been shown to degrade occludin.[37] This leads to further disruption of the BBB and BSCB[38]


References

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Further reading

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MMP3

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Matrix metalloproteinase 3 (MMP3), also known as stromelysin-1, is a zinc-dependent encoded by the on 11q22.3 that plays a central role in (ECM) degradation and tissue remodeling. The protein consists of 477 , featuring a , a propeptide domain that maintains latency, a catalytic domain responsible for proteolytic activity, a hinge region, and a hemopexin-like domain that aids in substrate specificity and inhibitor binding. MMP3 exhibits broad substrate specificity, cleaving ECM components such as proteoglycans, , , and collagens types III, IV, IX, and X, as well as non-matrix proteins like growth factors and other proteases, thereby facilitating processes like , embryonic development, and . MMP3 was first identified in the through its neutral proteinase activity in connective tissues, with the enzyme purified and characterized as a proteoglycanase in 1981–1983. It was subsequently recognized as stromelysin-1 and mapped to in the late 1980s, contributing to the understanding of the matrix metalloproteinase family. In physiological contexts, MMP3 is primarily expressed in connective tissues by cells such as fibroblasts, chondrocytes, and synovial cells, where it contributes to normal tissue and cell differentiation events, including , , and bone formation. Its activity is tightly regulated at transcriptional, translational, and post-translational levels; for instance, expression is induced by pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) through pathways such as and MAPK, while endogenous inhibitors like tissue inhibitors of metalloproteinases (TIMPs), particularly TIMP-1, and synthetic compounds help prevent excessive . Dysregulated MMP3 activity is implicated in numerous pathological conditions, including (where it promotes breakdown), (via synovial ), (contributing to plaque instability), and cancer progression (such as in and ovarian tumors, where it enhances invasion and ). Genetic polymorphisms in the MMP3 promoter, such as the 5A/6A insertion/deletion variant, have been associated with altered expression levels and increased susceptibility to diseases like coronary heart disease and . Ongoing research explores MMP3 as a for disease monitoring and a therapeutic target, with inhibitors showing promise in preclinical models of and .

Introduction

Definition and Nomenclature

Matrix metallopeptidase 3 (MMP3), also known as stromelysin-1 or transin, is a zinc-dependent that plays a key role in the degradation of (ECM) components. It is encoded by the human MMP3, which is the official symbol assigned by the HUGO Gene Nomenclature Committee (HGNC:7173). Other aliases for MMP3 include SL-1, STMY, STR1, CHDS6, MMP-3, and STMY1, reflecting its historical identification as a proteoglycanase and activator of other proteases. MMP3 belongs to the metzincin superfamily of , characterized by a conserved zinc-binding motif (HEXXHXXGXXH) in their . Within this superfamily, it is classified in clan MA, subfamily MA(M), family M10 (matrix metallopeptidases), and specifically peptidase M10.005. MMP3 is a member of the matrix metalloproteinase (MMP) family, which comprises over 20 related enzymes involved in ECM remodeling, and it is assigned to the stromelysin subfamily alongside MMP10 (stromelysin-2) and MMP11 (stromelysin-3). This subfamily is distinguished by their broad substrate specificity for non-collagenous ECM proteins, though MMP3 itself exhibits versatile proteolytic activity without preference for specific substrates in its general definition. The MMP3 gene and its protein product demonstrate evolutionary conservation across vertebrates, with orthologs identified in species ranging from humans to rodents, underscoring its fundamental role in tissue homeostasis. In humans, the gene is located on chromosome 11q22.3 as part of the MMP gene cluster, highlighting its integration within the broader MMP family nomenclature.

Discovery and History

Matrix metalloproteinase 3 (MMP3), also known as stromelysin-1, was first identified in the mid-1980s through independent studies on extracellular matrix-degrading enzymes. In 1985, Chin et al. described stromelysin as a connective tissue-degrading metalloendopeptidase secreted by stimulated rabbit synovial fibroblasts, highlighting its ability to degrade proteoglycans and other matrix components. Concurrently, Matrisian et al. cloned the gene for transin, a transformation-associated protein in polyomavirus-transformed rat fibroblasts, which was later recognized as the rat homolog of human stromelysin-1 or MMP3. These discoveries positioned MMP3 as a key player in tissue remodeling processes regulated by growth factors and oncogenic signals. The human MMP3 gene was cloned in 1986 by Whitham et al., who sequenced partial cDNAs from human fibroblasts and revealed its structural similarity to collagenase, including a proenzyme domain and zinc-binding catalytic site. Throughout the late and , early studies established MMP3's significance in (ECM) remodeling, particularly in pathological contexts such as tumor invasion and . For instance, research demonstrated elevated MMP3 expression in invasive breast carcinoma cells and synovial tissues from patients, linking it to degradation and joint destruction. A major milestone came in the mid- with the identification of a functional 5A/6A polymorphism in the MMP3 promoter by Ye et al., which influences transcriptional activity and was associated with accelerated progression. In the , investigations have expanded MMP3's historical narrative by uncovering its roles in reproductive . A 2022 study by Li et al. revealed that MMP3 derived from decidual macrophages contributes to ECM breakdown during spiral artery remodeling in early human pregnancy, facilitating invasion and vascular adaptation essential for placental development. These findings build on the enzyme's foundational , emphasizing its conserved function in dynamic tissue restructuring across physiological and states.

Molecular Structure and Genetics

Gene Location and Regulation

The MMP3 gene is located on the long arm of human at position 11q22.2 and spans approximately 7.8 kb, consisting of 10 exons that encode the precursor protein. The promoter region of the MMP3 gene features binding sites for transcription factors such as AP-1 and PEA3, which confer responsiveness to inflammatory cytokines including interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α), as well as to growth factors like (EGF). These elements enable inducible expression in response to extracellular signals, with AP-1 sites facilitating activation by phorbol esters and cytokines, while adjacent PEA3 sites enhance synergy with signaling pathways. A common functional polymorphism in the MMP3 promoter involves an insertion/deletion of residues at position -1171, resulting in 5A (deletion) or 6A (insertion) ; the 5A exhibits approximately 50% higher transcriptional activity compared to the 6A because the 6A binds more strongly as a transcriptional , leading to increased MMP3 expression in 5A carriers. Post-transcriptional regulation of MMP3 includes modulation of mRNA stability through AU-rich elements in the 3' , which promote rapid degradation under basal conditions, and interactions with microRNAs such as miR-143, whose upregulation in fibroblast-like synoviocytes enhances TNF-α-induced MMP3 expression alongside other proinflammatory mediators. MMP3 exhibits tissue-specific expression patterns, with prominent production in cells including fibroblasts, where it responds to inflammatory stimuli; synoviocytes in articular joints, contributing to remodeling; and macrophages, particularly in inflammatory infiltrates, where it supports tissue invasion and cytokine-driven responses.

Protein Structure

Matrix metalloproteinase 3 (MMP3), also known as stromelysin-1, is synthesized as an inactive proenzyme comprising 477 with a calculated of approximately 54 kDa. The protein exhibits a modular domain architecture typical of archetypal MMPs, consisting of an N-terminal (residues 1–17) that directs , a regulatory pro-domain (residues 18–97), a catalytic domain (residues 98–268), a flexible or linker region (residues 269–283), and a C-terminal hemopexin-like domain (residues 284–477). This organization facilitates targeted remodeling while maintaining latency until is required. The pro-domain plays a critical role in enzyme latency through its cysteine switch mechanism, where the conserved cysteine residue at position 102 (within the PRCGVPD motif) coordinates directly with the active-site zinc ion in the catalytic domain, preventing premature proteolysis. This interaction shields the catalytic machinery and ensures zymogen stability during biosynthesis and secretion. Upon activation, proteolytic cleavage disrupts this coordination, exposing the active site. The catalytic domain adopts a globular fold dominated by a twisted β-sheet , featuring the hallmark zinc-binding motif HEXXHXXGXXH (with histidines coordinating the catalytic Zn²⁺ ) and an adjacent Met-turn loop that positions substrates for . These elements form the active-site cleft, enabling activity against diverse components. The hemopexin-like domain, composed of four-bladed β-propeller repeats stabilized by bonds, extends from the catalytic domain via the and modulates substrate recognition and specificity; it also serves as a binding platform for endogenous inhibitors like tissue inhibitors of metalloproteinases (TIMPs). High-resolution crystal structures of the MMP3 catalytic domain, such as the in complex with TIMP-1 in PDB ID 1UEA, illustrate the compact β-sheet core flanked by surface loops that confer flexibility for inhibitor and substrate accommodation, highlighting conserved structural features across the MMP family.

Biochemical Properties

Catalytic Mechanism

Matrix metalloproteinase 3 (MMP3), also known as stromelysin-1, functions as a zinc-dependent , featuring a catalytic site with one catalytic ion and one structural ion, alongside three calcium ions that contribute to the stability of the catalytic domain. The catalytic is coordinated by three residues (His201, His205, and His211), which facilitate substrate binding and . Activation of MMP3 occurs through proteolytic cleavage of its pro-domain by enzymes such as trypsin or other MMPs, which disrupts the inhibitory cysteine-zinc coordination and exposes the catalytic zinc for substrate interaction. In the active form, a zinc-bound water molecule serves as the nucleophile, deprotonated by the conserved glutamate residue (Glu202) acting as a general base. This initiates the reaction mechanism with a nucleophilic attack on the peptide carbonyl carbon of the substrate, forming a tetrahedral gem-diolate intermediate that is stabilized by the zinc ion and auxiliary water molecules in the active site. The intermediate collapses through proton transfer from Glu202 to the amide nitrogen, leading to cleavage of the peptide bond, with the release of the carboxylate product as the rate-limiting step. MMP3 exhibits optimal activity at an acidic of approximately 6.0, which influences its calcium affinity and catalytic efficiency. The enzyme demonstrates specificity for substrates with hydrophobic residues, particularly , at the P1' position, and often small or hydrophobic residues at the P1 position, enabling cleavage of diverse components. Auxiliary water molecules further stabilize the by forming hydrogen bonds within the oxyanion hole, enhancing the overall efficiency of .

Substrates and Activation

Matrix metalloproteinase 3 (MMP3), also known as stromelysin-1, primarily targets non-collagenous components of the (ECM), including proteoglycans such as aggrecan, as well as , , and . It also mediates partial degradation of fibrillar and collagens, including types III, IV, IX, and X, thereby facilitating ECM remodeling without complete fibril solubilization. These substrate specificities position MMP3 as a versatile in turnover, where it cleaves bonds in hinge regions or non-helical domains to generate bioactive fragments that influence . In addition to ECM proteins, MMP3 plays a key role in the proteolytic cascade by activating other pro-matrix metalloproteinases through specific cleavage of their inhibitory prodomains. It converts pro-MMP1 () into its active form by removing the N-terminal propeptide, enabling subsequent degradation. Similarly, MMP3 processes pro-MMP7 (matrilysin) and pro-MMP9 (gelatinase B) to yield enzymatically active species, amplifying matrix-degrading activity in coordinated protease networks. This activation of zymogens underscores MMP3's function as a central regulator in the MMP family, promoting sequential enzymatic events during tissue repair and pathological remodeling. MMP3 is synthesized as an inactive (pro-MMP3) with a prodomain that maintains latency via a conserved residue coordinating the catalytic , known as the cysteine switch mechanism. Activation occurs through proteolytic removal of this prodomain via extracellular pathways, such as cleavage by serine proteases like or ADAMTS family members, which generate active MMP3 in the pericellular space. Cell-surface activation can be mediated by membrane-type MMPs, including MT1-MMP (MMP14), which facilitates localized pro-MMP3 processing during . Under denaturing or high-concentration conditions, pro-MMP3 exhibits autocatalytic potential, where partial unfolding exposes the scissile bond for self-cleavage. The activation of pro-MMP3 is tightly regulated by tissue inhibitors of metalloproteinases (TIMPs), which bind with high affinity to the of nascent MMP3, preventing prodomain cleavage and inhibiting downstream activity in a 1:1 stoichiometric complex. TIMP-1, in particular, forms stable associations that suppress MMP3 activation even at low concentrations, maintaining ECM . , MMP3 activation predominantly occurs in inflammatory microenvironments, where cytokines and upregulate pro-MMP3 expression and enhance proteolytic processing by recruited or other activators, contributing to acute responses in and .

Physiological and Pathological Roles

Normal Functions

Matrix metalloproteinase 3 (MMP3), also known as stromelysin-1, plays essential roles in maintaining tissue through (ECM) remodeling during physiological processes. In , MMP3 degrades damaged ECM components such as , , and proteoglycans, thereby creating pathways for and migration to promote re-epithelialization and tissue repair. Studies in dental pulp models demonstrate that MMP3 accelerates wound closure by generating epithelial basal cells and facilitating reparative dentin formation. Similarly, in skin wounds following treatment, MMP3 enhances efficiency when modulated by agents like calcium pantothenate, underscoring its catabolic yet reparative function in normal tissue regeneration. MMP3 contributes to skeletal development by participating in cartilage remodeling and , processes critical for formation and integrity. During maturation, MMP3 expression is dynamically regulated to break down hypertrophic cartilage matrix, enabling vascular invasion and at growth plates. In bone defect models, MMP3 localizes to sites of active matrix synthesis and degradation, reflecting its involvement in balancing ECM turnover for proper cartilage-to-bone transition. Histone deacetylase 3 (HDAC3) further supports this by suppressing MMP3 in chondrocytes to prevent excessive degradation, ensuring controlled remodeling during formation. In reproductive physiology, MMP3 derived from decidual macrophages facilitates spiral artery remodeling in early , a vital step for establishing adequate uteroplacental blood flow. This enzyme degrades vascular and ECM in arterial walls, allowing invasion and transformation into low-resistance vessels essential for fetal nutrition. Recent findings highlight MMP3's specific contribution from immune cells in the , promoting coordinated vascular adaptation without pathological . MMP3 indirectly supports in healthy tissues by proteolytically clearing perivascular ECM barriers, which facilitates endothelial cell sprouting and new vessel formation during development and repair. (VEGF) upregulates MMP3 expression in endothelial cells, enhancing matrix degradation to promote tube formation and vascular network expansion. This function is particularly evident in contexts like neovascularization, where MMP3 complements other proteases to ensure balanced angiogenic responses. Beyond its extracellular proteolytic activity, MMP3 exhibits intracellular functions through nuclear translocation, acting as a transcriptional co-regulator in s to maintain tissue homeostasis. Upon and nuclear import, MMP3 binds to the transcription enhancer sequence TRENDIC in the promoter of growth factor (CTGF/CCN2), a key modulator of ECM production and . This interaction transactivates CTGF/CCN2 expression independently of MMP3's enzymatic activity, influencing behavior in processes like repair and prevention. Overexpression of nuclear MMP3 enhances CTGF/CCN2-driven responses, highlighting its role in gene regulation for adaptive tissue responses.

Disease Associations

Matrix metalloproteinase 3 (MMP3), also known as stromelysin-1, is implicated in the pathogenesis of various inflammatory diseases through its role in excessive (ECM) degradation. In (RA), MMP3 levels are significantly elevated in serum and , contributing to synovial tissue destruction and breakdown, and serving as a for disease activity and radiographic progression. In (OA), MMP3 overexpression promotes degradation by targeting proteoglycans and , exacerbating joint damage in both preclinical models and clinical settings. MMP3 plays a critical role in cancer progression by facilitating tumor and through ECM remodeling. Elevated MMP3 expression is observed in , colon, , and oral cancers, where it enhances tumor cell migration and , with the 5A promoter polymorphism associated with increased risk and poorer prognosis in and oral cancers. In cardiovascular diseases, MMP3 contributes to , aneurysms, and by destabilizing atherosclerotic plaques and promoting vascular remodeling via ECM . In neurological disorders, MMP3 is involved in blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) disruption following (TBI) and (SCI), leading to increased permeability and . It also participates in neurodegeneration by activating microglial responses and contributing to apoptotic signaling in stressed neurons, with recent evidence linking it to progressive brain pathologies. Additionally, MMP3 influences through remodeling and ECM alterations that promote and metabolic dysfunction. In developmental anomalies, MMP3 polymorphisms are associated with nonsyndromic cleft lip and palate, affecting palatal shelf fusion via dysregulated ECM degradation. Genetic variations in MMP3, particularly the 5A/6A promoter polymorphism, correlate with disease susceptibility; the 5A , which enhances transcriptional activity, increases for and aneurysms, while the 6A allele is linked to higher atherosclerosis incidence and in certain populations. These polymorphisms briefly reference regulatory effects detailed in gene location studies, underscoring MMP3's variable expression in .

Therapeutic Implications

Inhibitors and Modulators

Endogenous inhibitors of matrix metalloproteinase 3 (MMP3) primarily include the tissue inhibitors of metalloproteinases (TIMPs), a family of four proteins that reversibly bind to the enzyme's catalytic zinc-binding site in a 1:1 stoichiometric complex, effectively blocking its activity. TIMP-1, TIMP-2, and TIMP-3 exhibit high-affinity binding to MMP3 with dissociation constants (Kd) in the nanomolar range, approximately 10^{-9} M, which underscores their role in tightly regulating MMP3 under physiological conditions. Additionally, serves as a broad-spectrum endogenous trap for MMP3 and other proteases, capturing the enzyme through a conformational change that sterically hinders substrate access, thereby preventing degradation. Synthetic inhibitors of MMP3 fall into broad-spectrum and selective categories, most of which target the catalytic to disrupt enzymatic function. Broad-spectrum agents like batimastat and marimastat, hydroxamate-based compounds, chelate the cofactor in the , inhibiting MMP3 along with other family members at low micromolar concentrations. For greater specificity, PD166793 represents an orally bioavailable inhibitor with nanomolar potency against MMP3 ( ≈ 0.012 μM), forming stable complexes primarily at the catalytic domain while showing reduced activity against other MMPs, which helps mitigate off-target effects. Natural modulators of MMP3 activity include compounds that either directly inhibit the enzyme or indirectly suppress its expression. Tetracyclines such as exert inhibitory effects by chelating the catalytic , reducing MMP3 proteolytic activity without broad dosing, and demonstrating efficacy in preclinical models of tissue remodeling. Polyphenols from , particularly epigallocatechin-3-gallate (EGCG), downregulate MMP3 expression at the transcriptional level by inhibiting signaling pathways, leading to decreased secretion in inflammatory contexts, with concentrations as low as 62.5 μg/mL achieving over 50% reduction in MMP3 levels. Development of MMP3 inhibitors has faced significant challenges, particularly from off-target inhibition of other MMP family members, resulting in side effects such as musculoskeletal syndrome observed in early clinical trials of broad-spectrum agents like marimastat. This syndrome, characterized by joint pain, stiffness, and inflammation, arises from disruption of normal turnover essential for maintenance. Recent advances as of 2025 include engineered TIMP variants designed for selective inhibition of individual MMPs, including MMP3, to improve specificity.

Clinical Applications

Serum and plasma levels of MMP3 serve as biomarkers for monitoring disease activity in (RA), where elevated concentrations correlate with joint inflammation and response to therapy. In cancer, particularly colorectal and malignancies, increased circulating MMP3 indicates tumor progression and potential, aiding in prognostic assessment. Additionally, genotyping of the MMP3 promoter polymorphism (5A/6A at -1612) enables risk stratification; the 5A is linked to higher transcriptional activity and increased susceptibility to conditions like and certain cancers, guiding preventive strategies. Therapeutic applications leverage MMP3 inhibition in clinical trials, such as adjunctive low-dose , which reduces MMP3 activity and improves remission rates when combined with . In , approaches silencing MMP3 expression, including siRNA delivery, have shown promise in preclinical tumor models by suppressing invasion and enhancing efficacy. Broad-spectrum MMP inhibitors like marimastat failed in Phase III trials for cancer due to musculoskeletal and lack of efficacy, highlighting off-target effects. In contrast, targeted MMP3 interventions, such as siRNA-mediated knockdown, demonstrate success in preclinical models by reducing tumor growth without systemic side effects. Emerging applications include MMP3 knockdown for after (ICH), where MMP3-null models exhibit reduced lesion size and neuronal death, suggesting potential post-injury interventions. In , plasma MMP3 levels emerge as a diagnostic for , with elevated concentrations in affected pregnancies enabling early detection across trimesters. As of 2025, MMP3 expression has been associated with lung disease severity in individuals with (PI*MZ genotype). Future directions emphasize , utilizing 5A/6A to tailor MMP3-targeted therapies, such as selecting patients with high-risk alleles for intensified monitoring or specific inhibitors in and cancer management.

References

  1. https://www.ncbi.nlm.nih.gov/gene/4314
  2. https://pmc.ncbi.nlm.nih.gov/articles/PMC8283010/
  3. https://www.uniprot.org/uniprotkb/P08254/entry
  4. https://pmc.ncbi.nlm.nih.gov/articles/PMC3469639/
  5. https://pubmed.ncbi.nlm.nih.gov/15576483/
  6. https://ejbc.kr/DOIx.php?id=10.4048/jbc.2020.23.e17
  7. https://www.ebi.ac.uk/merops/cgi-bin/pepsum?id=M10.005
  8. https://pmc.ncbi.nlm.nih.gov/articles/PMC7290342/
  9. https://pmc.ncbi.nlm.nih.gov/articles/PMC7608139/
  10. https://www.sciencedirect.com/science/article/abs/pii/S1357272507004104
  11. https://www.sciencedirect.com/science/article/pii/S1357272507004104
  12. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0009902
  13. https://pubmed.ncbi.nlm.nih.gov/16904077/
  14. https://www.nature.com/articles/s41413-023-00244-1
  15. https://www.sciencedirect.com/science/article/pii/S0021925819528848
  16. https://pmc.ncbi.nlm.nih.gov/articles/PMC1064889/
  17. https://www.sciencedirect.com/science/article/pii/S0006349507684707
  18. https://www.pnas.org/doi/10.1073/pnas.87.14.5578
  19. https://academic.oup.com/cardiovascres/article/69/3/562/272258
  20. https://www.rcsb.org/structure/1UEA
  21. https://doi.org/10.3390/cells9051076
  22. https://www.ebi.ac.uk/thornton-srv/m-csa/entry/591/
  23. https://www.ahajournals.org/doi/10.1161/01.res.0000070112.80711.3d
  24. https://journals.biologists.com/jcs/article/137/2/jcs261898/342431/Matrix-metalloproteinases-at-a-glance
  25. https://www.jbc.org/article/S0021-9258(19)61471-2/fulltext
  26. https://pmc.ncbi.nlm.nih.gov/articles/PMC2246078/
  27. https://pubmed.ncbi.nlm.nih.gov/19834065/
  28. https://pubmed.ncbi.nlm.nih.gov/33990899/
  29. https://pubmed.ncbi.nlm.nih.gov/14764345/
  30. https://pubmed.ncbi.nlm.nih.gov/27507649/
  31. https://pubmed.ncbi.nlm.nih.gov/35176662/
  32. https://pubmed.ncbi.nlm.nih.gov/14534780/
  33. https://pubmed.ncbi.nlm.nih.gov/18172013/
  34. https://www.sciencedirect.com/science/article/pii/S1110116416000028
  35. https://pmc.ncbi.nlm.nih.gov/articles/PMC10373173/
  36. https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-017-1449-z
  37. https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2021.663978/full
  38. https://www.oncotarget.com/article/18745/text/
  39. https://pmc.ncbi.nlm.nih.gov/articles/PMC8450250/
  40. https://pmc.ncbi.nlm.nih.gov/articles/PMC12025634/
  41. https://academic.oup.com/cardiovascres/article/69/3/636/272906
  42. https://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2010.07082.x
  43. https://www.sciencedirect.com/science/article/abs/pii/S0014488604004248
  44. https://www.dovepress.com/metalloproteinases-and-neurodegenerative-diseases-pathophysiological-a-peer-reviewed-fulltext-article-MNM
  45. https://www.mdpi.com/1422-0067/24/13/10649
  46. https://pmc.ncbi.nlm.nih.gov/articles/PMC4107548/
  47. https://pubmed.ncbi.nlm.nih.gov/17537400/
  48. https://www.spandidos-publications.com/mmr/3/5/735/download
  49. https://pubmed.ncbi.nlm.nih.gov/28781337/
  50. https://pmc.ncbi.nlm.nih.gov/articles/PMC2823312/
  51. https://www.sciencedirect.com/science/article/pii/S0021925822000941
  52. https://publications.ersnet.org/content/erj/40/3/766
  53. https://pmc.ncbi.nlm.nih.gov/articles/PMC1978261/
  54. https://www.medchemexpress.com/pd-166793.html
  55. https://www.sciencedirect.com/science/article/abs/pii/S1043661811001411
  56. https://www.nature.com/articles/srep34520
  57. https://www.mdpi.com/2218-273X/10/5/717
  58. https://aacrjournals.org/mct/article/17/6/1147/92406/Matrix-Metalloproteinase-Inhibitors-in-Cancer
  59. https://www.sciencedirect.com/science/article/abs/pii/S0968000425001914
  60. https://pubmed.ncbi.nlm.nih.gov/34121372/
  61. https://pmc.ncbi.nlm.nih.gov/articles/PMC10824561/
  62. https://www.cureus.com/articles/72022-association-of-matrix-metalloproteinase-mmp-gene-polymorphisms-with-knee-osteoarthritis-a-review-of-the-literature
  63. https://ejim.springeropen.com/articles/10.1186/s43162-021-00032-5
  64. https://www.nature.com/articles/nrd4390
  65. https://www.mdpi.com/1422-0067/26/9/4012
  66. https://academic.oup.com/brain/article/132/1/26/286037
  67. https://www.imrpress.com/journal/CEOG/52/9/10.31083/CEOG42755
  68. https://bmjopenrespres.bmj.com/content/12/1/e003585
  69. https://pmc.ncbi.nlm.nih.gov/articles/PMC416441/
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