BBA - Molecular Cell Research xxx (xxxx) xxxxxx

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BBA - Molecular Cell Research

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Review

Matrix metalloproteinase collagenolysis in health and disease

Sabrina Amara, Lyndsay Smitha, Gregg B. Fieldsa,b,
a
Department of Chemistry & Biochemistry, Florida Atlantic University, Jupiter, FL 33458, USA
b
Department of Chemistry, The Scripps Research Institute/Scripps Florida, Jupiter, FL 33458, USA

A R T I C L E I N F O A B S T R A C T

Keywords: The proteolytic processing of collagen (collagenolysis) is critical in development and homeostasis, but also
Arthritis contributes to numerous pathologies. Mammalian interstitial collagenolytic enzymes include members of the
Collagen matrix metalloproteinase (MMP) family and cathepsin K. While MMPs have long been recognized for their
Matrix metalloproteinase ability to catalyze the hydrolysis of collagen, the roles of individual MMPs in physiological and pathological
Metastasis
collagenolysis are less dened. The use of knockout and mutant animal models, which reect human diseases,
Skeletal defects
has revealed distinct collagenolytic roles for MT1-MMP and MMP-13. A better understanding of temporal and
Wound healing
spatial collagen processing, along with the knowledge of the specic MMP involved, will ultimately lead to more
eective treatments for cancer, arthritis, cardiovascular conditions, and infectious diseases. This article is part of
a Special Issue entitled: Matrix Metalloproteinases edited by Rafael Fridman.

1. Introduction
The matrix metalloproteinases (MMPs) are a family of Zn2 +-
dependent endopeptidases. MMPs were rst identied as enzymes
capable of catalyzing the hydrolysis of collagen [1]. MMP-mediated
collagenolysis has long been implicated in the physiological remodeling
of tissues and embryonic development as well as the progression of
disease pathologies. Inhibition of MMP collagenolytic activity has been
extensively pursued [24], but with little success in the clinic [57].
One of the limitations of previous inhibitor development was the lack of
recognition that some MMPs have host benecial functions that should
not be modulated if possible [811]. Systems biology approaches have
allowed for a more global view of MMP activities [1218], and insights
into the MMP collagenolytic mechanism [1921] has revealed possibi-
lities for selective inhibition of collagenolytic MMPs. The role of
specic MMPs in collagenolysis, and the relationship between collage-
nolysis and disease, has been better dened through the use of
knockout and mutant animal models.
2. Structural organization and assembly of interstitial collagens
Collagens are the most abundant proteins in the human body and
the main components of the extracellular matrix (ECM). The collagen
family is made up of at least 28 members [2224]. Collagens are
composed of three chains of primarily repeating Gly-Xaa-Yaa triplets,
which induce each chain to adopt a left-handed polyPro II helix.
Three chains then intertwine, staggered by one residue and coiled, to
form a right-handed superhelix [25,26]. Triple-helical structure pro-
vides collagens with exceptional mechanical strength, broad resistance
to the proteolytic enzymes, and a distinct topology for protein-protein
interactions [27].
Collagens have been classied according to their chains.
Homotrimeric collagens (i.e., types II and III) have three chains of
identical sequence. Heterotrimeric collagens have two chains of
identical sequence (designated 1) and one chain of diering
sequence (designated 2) (i.e., type I), or three chains with dierent
sequences (designated 1, 2, and 3) (i.e., type VI) [28]. Collagens
are further classied into subfamilies, based on their quaternary
structure. These subfamilies include brillar, bril associated with
interrupted triple-helices, short chain, basement membrane, multiplex-
ins, and membrane associated with interrupted triple-helices [28]. The
most common collagens (types I, II, III, V, and XI) have brillar
structures [29].
Types I, II, and III collagen compose the interstitial collagen
subfamily. Interstitial collagens are so named because of their proxi-
mity to cells in the extracellular space. Type I collagen, the most profuse
and ubiquitous of the collagens, is found in the majority of connective
and embryonic tissues [28,30]. Type II collagen is found in cartilage
and the vitreous humor [30]. Its expression also occurs during
embryogenesis. Type III collagen is found in visceral and cardiovascular
tissues [30], as well as in numerous tissues characterized by high type I
collagen content. Type V collagen is found associated with type I

This article is part of a Special Issue entitled: Matrix Metalloproteinases edited by Rafael Fridman.

Corresponding author at: Department of Chemistry & Biochemistry, Florida Atlantic University, 5353 Parkside Drive, Building MC17, Jupiter, FL 33458, USA.
E-mail addresses: samar@fau.edu (S. Amar), lyndsaysmith2015@fau.edu (L. Smith), eldsg@fau.edu (G.B. Fields).

http://dx.doi.org/10.1016/j.bbamcr.2017.04.015
Received 14 January 2017; Received in revised form 20 April 2017; Accepted 24 April 2017
0167-4889/ 2017 Elsevier B.V. All rights reserved.

Please cite this article as: Amar, S., BBA - Molecular Cell Research (2017), http://dx.doi.org/10.1016/j.bbamcr.2017.04.015
S. Amar et al.
collagen, while type XI collagen is associated with type II collagen
[31,32].
The triple-helical domains of types I, II, and III collagen span
10141023 residues. Each of these collagens also initially possess N-
and C-terminal non-triple-helical regions (propeptides). Following
synthesis, but before interstitial procollagen can be properly folded, a
series of post-translational modications must occur on the central
(Gly-Xaa-Yaa)n domain, including hydroxylation of most Pro and some
Lys residues in the Yaa position (by prolyl 4-hydroxylase, prolyl 3-
hydroxylase, and lysyl 5-hydroxylases) followed by glycosylation of
selective 5-hydroxylysine residues [3336]. Glycosylation also occurs
on some Asn residues in the C-terminal propeptides. Disulde bonds
between the propeptides are rearranged by protein disulde isomerase
and isomerization of Pro and 4-hydroxy-L-proline (Hyp) from cis to
trans takes place [3739]. Assembly and correct folding of procollagen
occurs within the endoplasmic reticulum [40]. Hsp47 stabilizes the
folded triple-helix [4143].
The C-terminal propeptides mediate interaction between three
chains and hold these chains in place, nucleating triple-helical forma-
tion. Lateral association of triple-helices occurs in the Golgi [40]. The
triple-helical molecules are then secreted from the cell and the N- and
C-terminal propeptides that ank the central (Gly-Xaa-Yaa)n domain
are removed. The resulting tropocollagen contains short N- and C-
terminal telopeptides and the central triple-helical domain. A disinte-
grin and metalloproteinase with thrombospondin motifs 2 (ADAMTS-2)
removes the N-terminal propeptide from types I, II, and III procollagens
[44]. ADAMTS-3 processes the N-terminal propeptide from type II
procollagen, while ADAMTS-14 processes the N-terminal propeptide
from type I procollagen [44]. Procollagen C-proteinase-2/bone mor-
phogenetic protein-1 cleaves the C-terminal propeptides from types I, II,
and III procollagens [45,46]. Meprins and also cleave procollagen
III N- and C-propeptides, releasing the mature protein which then
assembles into brils [47]. Cleavage by meprins is at the same site as
procollagen C-proteinase-2. Oxidation of Lys residues by lysyl oxidases
(LOXs) allows for the formation of intermolecular crosslinks, which
stabilize higher order structures such as brils and bers [48].
3. Am I a collagenase? MMPs that catalyze interstitial collagen
catabolism
Hydrolysis of interstitial collagens occurs by a limited number of
proteases. The scientic literature contains numerous examples of
proteases deemed collagenolytic, but this is often obscured by the
lack of criteria by which an enzyme is classied to eciently catalyze
the hydrolysis of an intact triple-helix. A collagenolytic enzyme should
be considered one that processes a triple-helix under conditions by
which that triple-helix is intact. One standard test for triple-helical
integrity is susceptibility to trypsin hydrolysis [49]. Some collagens
(type III) have more exible potential cleavage sites than others (type
I), and thus are more susceptible to hydrolysis by a variety of proteases
[5052]. A collagenolytic enzyme should thus process the triple-helix
eciently, i.e. with a reasonable kcat/KM value for soluble collagen or
specic activity for brillar collagen [53]. The brillar form of collagen
is more resistant to general proteolysis [54], and MMP hydrolysis of
brillar collagen has a higher activation energy than for soluble
collagen [55]. Collagenolytic activities between enzymes can also be
directly compared to determine relative eciencies of proteolysis.
Interstitial collagens have long been recognized as being hydrolyzed
by the classic collagenases, MMP-1, MMP-8, and MMP-13, into and
length fragments (Table 1 and Fig. 1) [53,5662]. All three of these
enzymes catalyze collagen hydrolysis eciently (Table 2), but their
relative activities towards interstitial collagens dier. MMP-1 has
greater catalytic activity on type III collagen as a substrate. At 25 C,
the MMP-1 collagen preference is III > I > > II [63]. MMP-8 pre-
ferentially cleaves type I collagen over types II and III collagen at 25 C
[63]. MMP-13 cleaves type II collagen 5- and 6-times faster than types I
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BBA - Molecular Cell Research xxx (xxxx) xxxxxx
and type III collagen, respectively, at 25 C [53].
There is some ambiguity as to the collagenolytic activity of the
gelatinase members of the MMP family, MMP-2 and MMP-9. MMP-2
has been reported to cleave types I, II, and III collagen [6466],
although other reports have brought into question how robust the type I
collagenolytic activity of MMP-2 is [67,68]. Recombinant MMP-9
(0.5 g) was found to cleave type I collagen (27 g) at 37 C after
72 h [69]. MMP-9 also digested type III collagen at 25 C following 98 h
treatment [69]. For MMP-2 and MMP-9, the interstitial collagen
cleavage site is the same as the classic collagenases (Table 1). For both
MMP-2 and MMP-9, type III collagen is a preferred substrate compared
with types I and II [65,69]. Most likely, MMP-2 and MMP-9 do not
contribute signicantly to interstitial collagen turnover in vivo, but
instead produce collagen fragments following the action of MMP-13 or
MT1-MMP (see below).
The ability of MMP-9 to cleave the intact triple-helix of type V
collagen has been reported [7072]. Conditions were 438-876 nM
MMP-9, 2 g human type V collagen for 30 h at 30 C [71], which
resulted in near complete digestion of the collagen, or 2243 nM MMP-
9, 1 g/L human type V collagen for 18 h at 30 C [72], which resulted
in more moderate digestion of the collagen. Although the cleavage sites
within type V collagen was identied by treatment at 30 C for 16 h, the
sites were slightly out of alignment within the [1(V)]22(V) hetero-
trimeric triple-helix (Table 1) [70].
Transfection of two membrane type-MMPs (MT-MMPs), MT1-MMP/
MMP-14 and MT2-MMP/MMP-15, allowed invasion-incompetent cells
to penetrate type I collagen matrices [73]. MT1-MMP processes types I-
III collagen at the same site as the classic collagenases (Table 1) [74].
MT1-MMP prefers type I collagen, as activity against type I collagen
was estimated to be 4 times that of type II collagen and 6.5 times that of
type III collagen [74].
Some studies indicated a requirement of MT1-MMP homodimeriza-
tion through the hemopexin-like (HPX) domain for ecient collageno-
lysis [75,76]. Alternatively, deletion of the HPX domain did not inhibit
collagen invasion modulated by cell surface-bound MT1-MMP [77,78].
In solution, MT1-MMP was not found as a dimer [21,79] and the MT1-
MMP HPX domain alone did not form a dimer [80]. The low level of
collagenolytic activity observed with an MT1-MMP HPX domain
mutant [81] may have been due to disruption of favorable MT1-MMP
interaction with the cell surface rather than dimer disruption [79]. The
conicting results in prior studies may result from dierent MT1-MMP
constructs being utilized. When MT1-MMP residues 336535 were
deleted (the resulting enzyme contained the CAT domain, the linker,
and 18 residues from the HPX domain), collagenolysis was inhibited
[76]. In this construct Cys318 is present; in the full-length MT1-MMP,
Cys318 forms a disulde bond with Cys507. When MT1-MMP residues
318535 were deleted (the resulting enzyme contained the CAT domain
and the linker), collagenolyis was still observed [77]. In this construct
there are no unpaired Cys residues. Ultimately, recent studies have
concluded that dimerization is not necessary for MT1-MMP catalyzed
collagenolysis [21,79], and that collagenolysis can occur without the
HPX domain when the enzyme is cell-surface bound [77,78].
MT3-MMP/MMP-16 was found to cleave type III collagen at the
classic site (Table 1), and was more ecient at processing type III
collagen than MT1-MMP (Table 2) [82]. Conversely, MT3-MMP did not
cleave types I and II collagen within their triple-helical domains [82].
Transfection of MT3-MMP either did not allow or only weakly allowed
invasion-incompetent cells to penetrate type I collagen matrices
[73,83]. Similar behavior was observed with MT3-MMP-expressing
WM852 melanoma cells [84]. However, in complete contrast, Shi et al.
found MT3-MMP to eciently process types I and II collagen lms [85].
The dierences in observed MT3-MMP collagenolytic activities may
originate from the constructs or cell types (MDCK cells [73,83], WM852
melanoma [84], and Cos-7 cells [85]) used.
MT6-MMP/MMP-25 was initially reported to have little or no
collagenolytic activity [86,87], but subsequently was found to cleave
S. Amar et al. BBA - Molecular Cell Research xxx (xxxx) xxxxxx

Table 1
Representative MMP and cathepsin K cleavage sites within collagen triple-helical domains.

Enzyme Collagen chain (collagen type) Sequencea

MMP-1, -2, -8, -9, -12, -13, MT1-MMP 1(I) Pro-Gln-Gly775 ~ Ile776-Ala-Gly
MMP-1, -2, -8, -9, -12, -13, MT1-MMP 2(I) Pro-Gln-Gly775 ~ Leu776-Leu-Gly
MMP-1, -8, -13, MT1-MMP 1(II) Pro-Gln-Gly775 ~ Leu776-Ala-Gly
MMP-1, -8, -9, -12, -13, MT1-MMP, MT3-MMP 1(III) Pro-Leu-Gly775 ~ Ile776-Ala-Gly
MMP-9 1(V) Pro-Pro-Gly439 ~ Val440-Val-Gly
MMP-9 2(V) Pro-Pro-Gly445 ~ Leu446-Arg-Gly
Cathepsin K 1(I) Gly-Pro-Arg9 ~Gly10-Leu-Pro
Cathepsin K 1(I) Gly-Pro-Gln21 ~ Gly22-Phe-Gln
Cathepsin K 1(I) Gly-Leu-Asp96 ~ Gly97-Ala-Lys
Cathepsin K 1(I) Gly-Pro-Gln189 ~ Gly190-Val-Arg
Cathepsin K 1(I) Gly-Pro-Ser810 ~ Gly811-Ala-Ser
Cathepsin K 2(I) Gly-Pro-Arg9 ~Gly10-Pro-Pro
Cathepsin K 2(I) Gly-Pro-Gln21 ~ Gly22-Phe-Gln
Cathepsin K 2(I) Gly-Leu-Lys99 ~ Gly100-Pro-Gln
Cathepsin K 2(I) Gly-Ala-Arg144 ~ Gly145-Ser-Asp
Cathepsin K 2(I) Pro-Pro-Gly814 ~ Ala815-Arg-Gly
Cathepsin K 1(II) Lys-Pro-Gly61 ~ Lys62-Ser-Gly

a
Numbering begins at the N-terminus of the triple-helical region of each collagen.

types I and II collagen (albeit at 37 C) [88] and a triple-helical peptide
model of the classic collagenase cleavage site in interstitial collagen
[89]. The MT6-MMP cleavage sites in the 1 and 2 chains of type I
collagen did not align, and many sites were located in the non-triple-
helical C-terminal telopeptide region [88]. This indicates that MT6-
MMP is not a truly collagenolytic protease.
The CAT domain of MMP-12 processes types I and III collagens at
33 C, where hydrolysis occurs at the classic cleavage site and at
numerous other sequences [90]. The classic collagenase cleavage site
seemed to be the most sensitive to MMP-12 (Table 1). However, we
found that MMP-12 could not cleave type I collagen eciently under
conditions comparable to other collagenases (Fig. 2). The observed
hydrolysis reported previously was most likely due to the combination
of high concentration of enzyme and substrate (10 g/mL of enzyme
with 1 mg/mL substrate), temperature (33 C), and time (24 h). In
similar fashion, although the MMP-12 catalytic domain has been
reported to cleave the triple-helix of type V collagen [91], we found
that it could not cleave type V collagen eciently (Fig. 3). The prior
study used 0.2 g of enzyme and 10 g of type V collagen at room
temperature for 16 h.
MMP-3 binds to type I collagen, but does not cleave the native
triple-helix [92,93]. However, the MMP-3 catalytic (CAT) domain can
cleave collagen when the triple-helix is destabilized by catalytically
inactive MMP-1 [94]. Thus, MMP-3 is entirely competent to cleave type
I collagen, but does not. Based on the MMP collagenolysis mechanism,
the linker needs to be able to properly orient the CAT and HPX domains
[1921]. Large domain movements based on the exible linker have
been observed for MMP-1, MMP-9, and MMP-12 [20,9598]. Gly272 is
critical for the collagenolytic activity of MMP-1, with its role proposed
to be the linker-bending motion that allows the HPX domain to present
collagen to the CAT domain [99,100]. MMP-1 and MMP-8 linkers are
considerably shorter than the MMP-3 linker, while MT1-MMP linker is
very long (33 residues), with signicant and heterogeneous O-glycosy-
lation [101]. Thus, linker length per se is not the ultimate criteria for
ecient collagenolysis. A chimeric MMP-8 whose linker region (16
residues) was replaced with the corresponding MMP-3 sequence (25
residues) lost activity towards collagen [102]. In similar fashion, MMP-
1/MMP-3 chimeras possessing the MMP-3 linker are not active towards
collagen [93,103]. The linker appears critical for proper alignment of
the CAT and HPX domains during collagenolysis. Ultimately, there may
be negative regulation of collagenolytic activity due to (mis)alignment
of the CAT and HPX domains in the case of MMP-3 and other non-
collagenolytic MMPs.
The intact triple-helix of interstitial collagen is cleaved eciently by
the cysteine protease cathepsin K under acidic conditions (optimum
pH 5.0) [104106]. Five distinct sites of cathepsin K hydrolysis of type I
collagen have been identied, as well as one in type II collagen (Table 1
and Fig. 1) [105,107].
To determine am I a collagenase?, the most prudent approach is to
compare an enzyme to a known collagenase (such as MMP-1) and a

Fig. 1. Schematic representation of MMP and cathepsin K cleavage sites in type I collagen. The bold, solid green arrow indicates the known MMP cleavage site (bond 775776) aligned in
all three chains in the triple-helix. The bold, dashed green arrows indicate the cathepsin K cleavage sites where all three chains in the triple-helix align (bonds 910 and 2122; see
Table 1). The dashed green arrows indicate the cathepsin K cleavage sites in individual collagen chains that do not align within the triple-helix (see Table 1). For cleavage by cathepsin K
within individual chains, sites in the 1(I) chain are noted above the triple-helix, while cleavage sites in the 2(I) chain are noted below the triple-helix.

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S. Amar et al. BBA - Molecular Cell Research xxx (xxxx) xxxxxx

Table 2
Kinetic parameters for human collagen hydrolysis by MMPs.

Collagen type Enzyme kcat/KM (s 1 M 1) KM (M) kcat (s 1) Assay T (C) Reference

I MMP-1 14,600 0.82 0.012 30 [56]

I MMP-1 18,750 0.80 0.015 30 [56]
I MMP-1 525,000 0.9 0.472 37 [243]
Ia MMP-1 742,000 0.31 0.23 27 [244]
Ib MMP-1 4,740 1.3 0.00617 27 [74]
Ic MMP-1 4,610 1.0 0.00461 25 [64]
Ic MMP-2 529 8.5 0.00450 25 [64]
I MMP-8 2,540 0.7 0.00178 25 [63]
Ia MMP-8 2,260,000 0.21 0.470 37 [245]
Ib MT1-MMP 680 2.9 0.00197 27 [74]
II MMP-1 132 2.1 0.00028 25 [246]
II MMP-8 593 1.1 0.00065 25 [63]
III MMP-1 112,000 1.4 0.157 25 [50]
III MMP-1 118,000 1.3 0.153 25 [50]
IIId MMP-1 93,000 15 1.4 25 [247]
IIIe MMP-1 59,000 1.3 0.08 25 [52]
III MMP-8 131 1.8 0.00024 25 [63]
IIId MMP-13 22,600 14 0.32 25 [247]
III MT1-MMP 366 0.95 0.00035 27 [82]
III MT3-MMP 1,926 0.45 0.00087 27 [82]

a
Bovine type I collagen.
b
Guinea pig type I collagen.
c
Rat type I collagen.
d
Human type III collagen sequence inserted into bacterial collagen.
e
Recombinant type III collagen expressed in P. pastoris.

non-collagenolytic protease (such as trypsin) using gel-based analysis of
collagen degradation (as shown in Figs. 2 and 3). One can readily
monitor the disappearance of the intact collagen chains over time to
evaluate kinetic parameters. Active enzyme concentrations should be
comparable on a molar basis, and an appropriate temperature used
whereby there is no collagenolysis by the non-collagenolytic protease.
For cell surface-bound enzymes, comparisons to MT1-MMP-producing
or -transfected cells can be performed for invasion of collagen matrices
or processing of collagen lms. In lieu of titrating the amount of active
enzyme on the cell surface (which can be quite dicult), total protein
concentration of the enzyme and MT1-MMP should be comparable.
4. The role of collagen catabolism in normal physiology
The proteolysis of collagen is integral for numerous physiological
functions including morphogenesis, tissue remodeling, and wound
healing. Determining which MMPs participate in collagenolysis is
dicult, based on the fact that MMPs have multiple activities beyond
collagenolysis. For example, MT1-MMP participates in collagenolysis,
shedding of cell surface biomolecules, hydrolysis of serum proteins,
cytokines, brillar amyloid -protein, bronectin, Notch1, and the
laminin-5 2 chain, and activation of proMMP-2 and the pro-v
integrin subunit [108125]. MT1-MMP is also active intracellularly,
processing centrosomal breast cancer type 2 susceptibility gene (BRC-
A2) and pericentrin, where the latter event leads to chromosomal
instability [126,127]. In addition, collagen hydrolysis by MMPs has
other eects, such as directly disrupting the bronectin binding site
[128] and revealing cryptic binding sites within collagen chains
[129132]. Bulk collagenolysis may be performed by several MMPs
in a redundant and compensatory fashion [78]. However, the ultimate

Fig. 2. Cleavage of type I collagen by MMP-1 CAT domain, full-length MMP-1, MMP-12 CAT domain, and trypsin. Type I collagen (10 g) was treated with 200 ng of enzyme in 50 mM
TrisHCl, pH 7.5, 150 mM NaCl, 5 mM CaCl2, 0.05% Brij35, 1 M ZnCl2 for 36 h at either room temperature or 33 C. Full-length MMP-1 (MMP1 FL) cleaved type I collagen at room
temperature, resulting in the characteristic and fragments, while MMP-1 CAT domain (MMP1cat) showed a low level of hydrolysis and MMP-12 CAT domain (MMP12cat) did not
cleave the collagen. At 33 C, increased hydrolysis by MMP-1 CAT domain and a low level of hydrolysis by MMP-12 CAT domain was observed. Trypsin showed minimal collagen
hydrolysis at either temperature. Contr is type I collagen alone.

4
S. Amar et al.
Fig. 3. Cleavage of type V collagen by MMP-12 CAT domain (top) and trypsin (bottom). Type V collagen (333 nM) was treated with 432 nM of MMP-12 or 0.54 nM of trypsin in 50 mM
TrisHCl, pH 7.5, 150 mM NaCl, 5 mM CaCl2, 0.05% Brij35, 1 M ZnCl2 overnight at either room temperature (gels on the left) or 37 C (gels on the right). MMP12 CAT domain or trypsin
catalyzed the hydrolysis of type V collagen at 37 C, but not at room temperature. Lad is the molecular weight ladder, Col V is type V collagen alone, and Enzm is trypsin alone.
products of collagenolysis and their eects on cellular behaviors dier
based on the specic MMP [132]. Precise roles for collagen catabolism
have been ascertained from MMP knockout mice or mutant collagen
mice.
There are several pathways that have been considered for mamma-
lian collagen catabolism [62]. One pathway involves initial extracel-
lular MMP hydrolysis of collagen brils, followed by the large collagen
fragments undergoing urokinase plasminogen activator receptor-asso-
ciated protein (uPARAP)/Endo180-mediated (on mesenchymal cells)
and mannose receptor-mediated (on macrophages) endocytosis, lyso-
somal delivery, and cathepsin catalyzed degradation [133136]. The
initial collagen proteolysis has been ascribed to MT1-MMP [133,137].
Knockout studies showed that MT1-MMP has a variety of roles in
skeletal development, as aberrant cranial bone formation was observed
at birth in MT1-MMP knockout mice, and over time osteopenia
increased and bone mass decreased [138]. These eects were attributed
to a lack of interstitial collagenolytic activity of MT1-MMP [138,139],
as the knockout mice exhibited increasing brosis in tendons, liga-
ments, synovial capsules, musculotendinal junctions, and septal/fascial
structures and persistence of parietal cartilage [138]. The skeletal
defects may also have contributions from the lack of other proteolytic
activities of MT1-MMP, or indirect eects of decreased collagenolysis,
such as the lack of regulation of bronectin binding to collagen (see
above). A mutation in the signal peptide (Thr17Arg) results in
decreased production of active MT1-MMP in Winchester Syndrome
[140]. The mutation is hypothesized to aect MT1-MMP transport to
the cell membrane [140]. Winchester Syndrome is characterized by
osteolysis, or vanishing bone syndrome, whose skeletal phenotype
parallels that observed in the MT1-MMP knockout mouse [140].
MT3-MMP also contributes to skeletal development [85]. MT1-
MMP/MT3-MMP double deciency mice have severe craniofacial
dysmorphism and shortening of cortical bone beyond that observed in
MT1-MMP knockout mice. These contributions of MT3-MMP are
proposed to be a result of the collagenolytic activity of the enzyme
(see above) [85].
Knockout studies indicated that MMP-13 functions in skeletal
growth plate development (the transition from cartilage to bone)
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BBA - Molecular Cell Research xxx (xxxx) xxxxxx
[141]. More specically, in the knockout mice growth plates had a
lengthened hypertrophic chondrocyte zone and trabecular bone was
increased over time [141]. The lack of MMP-13 to process cartilage type
II collagen was key to these eects [139,141]. A mutation in the
propeptide of MMP-13 (Phe56Ser) results in the Missouri variant of
spondyloepimetaphyseal dysplasia (SEMD), a human disorder [142].
The mutant MMP-13 is degraded intracellularly [142]. SEMD is
characterized by abnormalities in development and growth of endo-
chondral skeletal components [141,142]. An Arg792Gly mutation in
type II collagen results in SEMD congenita [143]. This mutation has
been suggested to negatively aect the MMP HPX domain interaction
with the P17 subsite of collagen [144] and hence decrease collagen
turnover. Alternatively, it has also been proposed that the mutation
results in increased binding of type II collagen to bronectin and poor
ECM assembly [145].
MT1-MMP knockout mice have arrested tendon development
around the time of birth [146]. The knockout mouse tendons had
collagen brils of ~ 50 nm diameter that were retained by bripositors
(actin-dependent invaginations of the plasma membrane). It was
determined that collagenolysis by MT1-MMP was not essential for
tendon development, but MT1-MMP processing of bronectin was,
resulting in the release of brils from bripositors [146].
Substitution of Pro for Gln774 and Ala777 in the Col1a-1 gene results
in the production of type I collagen resistant to MMP-1, MMP-8, and
MT1-MMP processing [147149]. Introduction of this MMP resistant
type I collagen in mice did not aect development to young adulthood
[150]. MMP-13 cleaved the N-terminal telopeptide region of the
resistant type I collagen [151,152]. The relatively mild eects of the
mutant collagen on development to young adulthood may be due to
release of triple-helices from brils by aminotelopeptidase activity
[150], denaturation of the isolated triple-helices at body temperature
[153], and general proteolysis of isolated chains. However, after
36 months of age, mice displayed thickened skin with dermal brosis
[150]. Additionally, postpartum involution of the uterus was impaired
in female mice bearing the mutant collagen [150]. The uteri were lled
with nodules consisting of primarily type I collagen bers [150]. Thus,
it was proposed that cleavage in the N-terminal telopeptide region
S. Amar et al.
contributed to remodeling of type I collagen during development to
young adulthood, but cleavage within the triple-helix was needed for
remodeling during adulthood [151]. This may be due to collagen cross-
linking over time.
Skeletal remodeling was altered in the collagen mutant mice, with
increased calvarial periosteal and tibial/femoral endosteal bone deposi-
tion observed at 312 months of age [154]. Osteocyte/osteoblast
apoptosis occurred in the collagen mutant mice starting at 2 weeks of
age [154]. It has been proposed that MMP-derived collagen cleavage
products are anti-apoptotic [131,141,155]. This may be the reason that
parathyroid hormone induction of osteoclastic bone resorption is
greatly reduced in the collagen mutant mice [156]. Failure to degrade
type I collagen impaired hepatic stellate cell apoptosis and may prevent
the eective restoration of hepatocyte mass in liver brosis [157].
Wound healing, reepithelization, and contraction were delayed in the
rst 2 weeks after injury in type I collagen mutant mice [158]. The
number of contractile myobroblasts in the wound was decreased, and
thus dierentiation of broblasts to myobroblasts was impaired [158].
The signal to produce smooth muscle actin to generate tensile force to
contract the tissue was not received [158]. It is possible that apoptosis,
as described above, may be the reason why wound healing is impaired
[158]. In addition, MMP-1 processing of type I collagen has been shown
to promote keratinocyte migration during reepithelialization
[159,160].
For the mutant collagen studies, the precise MMP involved was not
identied. As described above, specic roles for MT1-MMP and MMP-
13 collagenolysis have been identied. MT1-MMP also contributes to
postnatal vascular development and skin homeostasis by cleaving type I
collagen [139,161]. MT1-MMP does not appear to be the critical
collagenase for wound repair [161].
Cathepsin K deciency resulted in pycnodysostosis, a bone-scleros-
ing dysplasia [162]. Undigested collagen brils are observed in
osteoblasts and broblasts during pycnodysostosis [163,164]. Patients
treated with the cathepsin K inhibitor balicatib exhibited skin hard-
ening, which was correlated to thickened collagen bundles and a
hypocellular and hypovascular dermis [165].
5. The role of collagen catabolism in disease
The proteolysis of collagen has been recognized as a contributing
factor to multiple pathologies, including tumor cell spreading (metas-
tasis), arthritis, glomerulonephritis, periodontal disease, tissue ulcera-
tions, cardiovascular disease, and neurodegenerative diseases
[166171].
It has long been demonstrated that tumor extracts can possess
collagenolytic activity [61,171,172]. MT1-MMP is the dominant peri-
cellular collagenase operative in vivo enabling cells to migrate through
connective tissue matrices where collagens exist as insoluble bers
[121,173175]. MT1-MMP appears to play a signicant role in tumor
metastasis [173,176,177]. Interestingly, even though MT1-MMP is an
interstitial collagenase, in similar fashion to several secreted MMPs
(MMP-1, MMP-8, and MMP-13), the activity of MT1-MMP, but not of
secreted collagenases, is critical for transmigration of tumor cells,
endothelial cells, and broblasts through collagen matrices
[73,78,178183]. Tumor cell invasion through type I collagen is
dependent upon MT1-MMP activity [182]. Collagen degradation by
MT1-MMP results in cryptic Arg-Gly-Asp sites being revealed and
binding to the v3 integrin. Integrin ligation then activates ERK
through c-Src, which in turn causes tumor cell proliferation [184].
MT1-MMP collagenolysis has been correlated to metastasis in vivo
[176]. Additional roles for collagenolysis in tumor progression have
been described [185], including participation of MMP-1 collagenolytic
activity in metastasis [186].
Homotrimeric type I collagen is produced by a variety of tumor cells
but not cancer-associated broblasts [187]. Homotrimeric type I
collagen is highly resistant to collagenolytic MMPs [188], and wild
6
BBA - Molecular Cell Research xxx (xxxx) xxxxxx
type broblasts degraded heterotrimeric type I collagen matrices but
not homotrimeric type I collagen matrices [187]. Homotrimeric type I
collagen enhances tumor cell proliferation and migration compared
with heterotrimeric type I collagen. It has been suggested that tumor
cells might use MMP-resistant homotrimeric type I collagen bers as
roadways for invasion [187].
Matrix stiness has been implicated in tumor progression, with
collagen considered a signicant contributor to changes in the cellular
mechanical microenvironment [189,190]. Increased orientation of
interstitial and brillar collagens, and increased stiness, is seen in
the invasive front of human breast cancer [190]. Transforming growth
factor (TGF-) enhances collagen deposition in breast and pancreatic
cancers [190,191], and TGF- can be activated by MMP-2, MMP-9, and
MT1-MMP [192195]. Increased matrix tension due to LOX cross-
linking of collagen induces integrin signaling [196]. In turn, inhibition
of LOX activity impedes breast tumor progression [196]. Mechano-
transduction and oncogenic signaling pathways may be synergistic in
promoting tumorigenicity [189], and there is mechanical heterogeneity
within tumors [190]. While intact collagen is required for signaling and
matrix stiness, MMP degradation of collagen facilitates tumorigenesis
[189]. LOX and MMPs most likely collaborate to create a dynamic
collagen-based microenvironment [189].
Osteoarthritis (OA), the most common form of arthritis, is char-
acterized by the destruction of articular cartilage. The main constitu-
ents of articular or joint cartilage are type II collagen and various
proteoglycans, such as aggrecan, chondroitin sulfate, and hyaluronan
[197]. Tensile strength of articular cartilage is due to the triple-helical
structure of type II collagen [198]. In native joint cartilage, type II
collagen brils are protected from cleavage by tight association with
molecles of aggrecan [199]. In arthritic cartilage, aggrecan is hydro-
lyzed by ADAMTS-1, ADAMTS-4, and ADAMTS-5, collectively known as
aggrecanases [200]. Aggrecanolysis removes aggrecan molecules from
type II collagen brils, which makes collagenolysis possible.
MMP-13 has been shown to be the main collagenase responsible for
degradation of articular cartilage during OA [201,202]. Under normal
circumstances, MMP-13 is constitutively produced in human chondro-
cytes, but is rapidly endocytosed and degraded [203,204]. MMP-13 is
specically expressed in the cartilage of human OA patients and is not
present in normal cartilage. MMP-13 synovial uid levels correlate to
human OA severity [205]. Furthermore, transgenic animal models
indicate that overexpression of MMP-13 induces joint abnormalities
characteristic of human OA [206]. More specically, mice expressing
an inducible transgene of spontaneously active MMP-13 had increased
cartilage collagen cleavage and OA progression [202]. Studies with
semi-selective and selective MMP-13 inhibitors demonstrated that
MMP-13 inhibition renders protection to human and bovine cartilage
cultures as well as providing chondroprotective eects in vivo
[206,207]. Cathepsin K has also been implicated in broblast-mediated
degradation of type II collagen in cartilage [208].
Osteoporosis (OP) is a chronic skeletal disease that is predicted to
aect nearly 61 million women over the age of 50 in the United States
by the year 2020 [209]. The skeletal density is dependent on constant
bone remodeling events, which are regulated by the balance of
osteoblast bone building and osteoclast resorptive actions. Bone is
primarily comprised of type I collagen which is mineralized via the
deposition of apatite during its synthesis by osteoblasts. Estrogen
deciency increases osteoclast formation by increasing the levels of
available pro-osteoclastogenic cytokines [210,211]. Osteoblastic cells
have been shown to secrete multiple MMPs, including MMP-2, MMP-3,
MMP-8, MMP-9, MMP-13, and MT1-MMP, while MMP-9 is mainly
expressed by osteoclasts [212]. These MMPs have been shown to be
capable of degradation of the osteoid that covers the bone trabeculae
and to initiate or activate bone remodeling in mice, rats, and humans
[213,214]. MMP-13 is mainly associated with mineralized bone matrix,
is thought to be essential for osteoclastogenesis, and plays an important
role in degradation of type I collagen in bone matrix in concert with
S. Amar et al.
cathepsin K and MMP-9 [212]. One of the mechanisms of estrogen
deciency-induced bone loss is ascribed to the abnormal expression of
multiple MMPs in osteoblastic cells, as estrogen inhibits bone resorption
and reduces bone turnover rate by down-regulating the expression of
MMP-13 in osteoblastic cells [214].
The selection of MMP-13, as opposed to other proteases, as a target
in OA and OP is well justied. For example, cartilage degradation is
reversible in the presence of aggrecanase activity, but not once type II
collagen degradation has proceeded [215]. Inhibition of cathepsin K,
which has been pursued for OP, may indiscriminately prevent normal
collagen turnover outside of the skeletal system [216].
During pathological vessel remodeling, neointimal lesions and
subsequent occlusive events found in atherosclerosis and postangio-
plasty restenosis result from MT1-MMP activity [217]. Vascular smooth
muscle cells use MT1-MMP to degrade and inltrate three-dimensional
collagenous barriers including the arterial wall (which is rich in type I
collagen) [217]. Amongst several causes, atherosclerotic plaque vulner-
ability (rupture) has been postulated to result from processing of
interstitial collagens in the brous cap of the plaque [218]. It is
presently not clear which collagenase (MMP-1, MMP-8, and/or MMP-
13) contributes to plaque instability [218].
Increased collagen synthesis over catabolism can result in myocar-
dial brosis, leading to ventricular hypertrophy and diastolic dysfunc-
tion [219]. In contrast, increased collagen catabolism over synthesis
can lead to ventricular dilatation and systolic dysfunction [219]. MT1-
MMP myocardial levels are increased post-myocardial infarction (MI)
and coincident with adverse left ventricular remodeling [220,221].
MT1-MMP is the dominant collagenase within myocardial tissues
[221]. Following MI, MT1-MMP+/ mice have a survival advantage
over MT1-MMP+/+ mice, while post-MI survival is reduced when MT1-
MMP is overexpressed [220]. Survival has been correlated to decreased
collagenolytic potential of cardiac broblasts (preservation of myocar-
dial type I collagen network) [221]. Liberation of collagen fragments
and subsequent processing by MMP-9 can help or hinder left ventricle
remodeling post-MI, depending upon the timing and extent of MMP-9
action [222,223].
Pulmonary brosis occurs following repeated bouts of lung injury,
as observed in cystic brosis, usual interstitial pneumonitis (UIP)/
idiopathic pulmonary brosis (IPF), and acute respiratory distress
syndrome (ARDS). Pulmonary brosis corresponds to excess collagen
production compared with degradation. [224]. Fibrosis may be the
result of a change in collagen composition, resulting in decreased
degradation, or an increase in the production of protease inhibitors. A
greater proportion of type I collagen compared with type III collagen is
observed in lung brotic tissue compared to normal lung tissue. Fibrotic
tissue also has increased amounts of collagen binding biomolecules,
such as bronectin and proteoglycans, increased proportion of hydro-
xylated Lys residues within the collagen, and an increase in collagen
crosslinking via LOX. An increased tissue inhibitor of metalloproteinase
(TIMP) to MMP ratio and decreased collagenolysis in the lung is found
in human UIP/IPF patients. Knockout studies have implicated MT1-
MMP and cathepsin K as key collagenases in brosis [224].
Inducible deletion of MT1-MMP in stromal broblasts was used to
examine the role of this enzyme in skin brosis [161]. Deletion of MT1-
MMP resulted in increased type I collagen accumulation in skin due to a
lack of collagen degradation, and a subsequent continuous increase in
skin thickness and stiness. Fibrosis was entirely due to the lack of
collagen turnover, as collagen bril diameters did not increase [161].
MT1-MMP also contributes to tissue damage and mortality in
infectious diseases. Tuberculosis, once the leading cause of death in
the U.S., remains a global threat due to limited treatment options, high
percentage of infection transmission, and increasing Mycobacterium
tuberculosis resistance [225]. The interaction between the Mycobacter-
ium tuberculosis bacteria and the host immune response (macrophage
infection) evokes inammation and breakdown of the pulmonary ECM
leading to formation of granulomas, the hallmark of the disease [226].
7
BBA - Molecular Cell Research xxx (xxxx) xxxxxx
Granulomas, formed by aggregates of lung epithelial and immune cells,
were once thought to curtail the spread of the disease by encasing
Mycobacterium tuberculosis. However, recently it has been shown that
infected macrophages shuttle between granulomas and the lung surface
in order to recruit uninfected macrophages. Upon arrival in the
granulomas, newly attracted macrophages become infected by the
bacteria and further propagate the infection [225].
MT1-MMP expression is upregulated in Mycobacterium tuberculosis-
infected macrophages [227]. MT1-MMP is signicantly upregulated in
patients with pulmonary tuberculosis, expressed throughout granulo-
mas, upregulated by monocyte-monocyte networks, and is functionally
active [226]. This upregulation was correlated to local tissue degrada-
tion (including collagen destruction) and leukocyte recruitment to the
granuloma, contributing to the disease pathology [226].
The lung epithelial barriers, supported by the ECM scaold and
functioning as the rst line of defense against pathogens, are severely
damaged during viral infections [228,229]. Uncontrolled immune-
mediated ECM-remodeling events act as a double-edged sword, allow-
ing multiple immune cells to inltrate the infection focus while causing
devastating collateral damage that promotes acute respiratory failure.
Global genomics analysis of lung tissue derived from an H1N1 inuenza
mouse model detected extremely elevated ECM remodeling collagenase
genes (mostly MT1-MMP) without a corresponding increase in TIMP-2
[230]. Follow-up experiments, including uorescence-correlated elec-
tron microscopy of intact tissues [231], global mass spectrometry,
immune staining, and tissue zymography, revealed dramatic morpho-
logic and compositional ECM changes in inuenza-infected lungs,
including depletion of brillar collagens [230]. The majority of the
MT1-MMP-expressing cells during the infection were immune cells of
myeloid origin. Remarkably, mice receiving Tamiu exhibited a
devastating ECM phenotype, despite having extremely low viral titers
[230]. Mice treated with an anti-MT1-MMP Fab fragment [232] showed
tissue recovery, both at the level of morphology and composition
(including improved collagen component abundance), and therapeutic
eects [230]. The two mouse models used were inuenza A infection
and inuenza A co-infected with Streptococcus pneumoniae [230].
Treatment with anti-MT1-MMP Fab fragment signicantly increased
the ability of virally infected mice to ght o secondary Streptococcus
pneumoniae bacterial infection over control. This was demonstrated by
the nding that 50% of the mice receiving the anti-MT1-MMP Fab
fragment survived the double-infection, whereas 100% of the mock
treated mice died. Mice that did not receive the inhibitor exhibited
bacteremia and dissemination of Streptococcus pneumoniae bacteria into
the spleen and liver, whereas the infection of treated mice remained
conned within the lungs, with no systemic bacterial dissemination
[230]. The results suggested that the ECM damage is caused by
inltrating immune cells contributing to the lethal outcome from
inuenza infection. Immune cell invasion and respiratory failure
depended on tissue damage, presumably by MT1-MMP. Blocking
MT1-MMP dysregulated collagenolytic activity in vivo and prompted a
therapeutic eect in both primary and co-infected disease stages/
models.
Mutations of type I collagen genes have been identied in osteogen-
esis imperfecta (OI) [22,28,32,39,233,234]. OI dominant-negative
mutations can occur in either gene that encode the chains of type I
collagen and are typically missense mutations that change the Gly
codons in the triple-helical motifs. Gly substitutions result in dierent
eects on helix stability, depending on their location and the newly
substituted amino acid. Mutations near the MMP cleavage site,
particularly in the 1(I) chain, often result in severe forms of the
disease [235]. This may be due to rendering the cleavage site
susceptible to proteases that are normally inhibited by triple-helical
structure. We have found that decreasing the thermal stability of the
MMP cleavage site renders it more susceptible to MMP-2 and MMP-9
hydrolysis [236].
MMP processing of type I collagen can ultimately result in the
S. Amar et al.
production of numerous, distinct fragments (see prior discussion). One
fragment resulting from collagenolysis, CO1-764/C1M (Gly-Ser-Pro-
Gly-Lys-Asp-Gly-Val-Arg-Gly586; numbering based on the 1(I) chain
triple-helical region), is generated by the action of MMP-13, MMP-2,
and/or MMP-9 [237]. It is presumed that a collagenase rst cleaves
type I collagen at the 775-776 bond (see Table 1), followed by MMP-13,
MMP-2, and/or MMP-9 action at the 586587 bond of the denatured
1(I) chain. CO1-764/C1M was proposed as a biomaker for liver
brosis [237]. Serum levels of C1M were found to be predictive of
increased mortality in women up to 9 years prior to death, while no
correlation was observed for a cathpesin K generated type I collagen
fragment (CTX-1) and mortality [238]. The most prevalent primary
causes of death in the study were cancer and cardiovascular disease
[238]. Increased C1M levels in the serum has been associated with
chronic inammation [238], and recent studies have focused on the
interrelationships between chronic inammation and numerous dis-
eases, including cancer and vascular diseases, as well as the role of
MMPs in inammation [11,194,239].
The peptide Pro-Gly-Pro is generated by the initial processing of
type I or II collagen by neutrophil MMP-8, followed by the proteolytic
action of MMP-9 and prolyl endopeptidase [240,241]. Pro-Gly-Pro is a
neutrophil chemoattractant and induces production of superoxide
[242]. Pro-Gly-Pro has been implicated in neutrophilic inammation
in lung diseases such as cystic brosis and chronic obstructive
pulmonary disease (COPD) [240,242].
6. Summary
The role of specic MMPs in collagenolysis has been better dened
through the use of animal models and the correlation of animal studies
with human diseases. The processing of collagen by MT1-MMP is now
associated with metastasis and progression of tuberculosis and inuen-
za to the lungs. In turn, MMP-13-mediated collagenolysis contributes
signicantly to osteoarthritis as well as normal bone development,
while collagen turnover by MMP-1 is a contributor to wound healing.
As we improve our understanding of temporal and spatial collagen
processing, along with the knowledge of the specic MMP involved, we
will ultimately be able to design more eective treatments for cancer,
arthritis, cardiovascular conditions, and infectious diseases.
Transparency Document
The Transparency document associated with this article can be
found, in online version.
Acknowledgments
We gratefully acknowledge the National Institutes of Health
(CA98799, AR063795, MH078948, and NHLBI contract
268201000036C), the Multiple Sclerosis National Research Institute,
the Robert A. Welch Foundation, and the Lustgarten Foundation for
support of our laboratory's research on MMPs. We thank Dr. Anna
Knapinska for creating Fig. 1.
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