Matrix Metalloproteinases and Their Inhibitors in Turnover and Degradation of Extracellular Matrix - Extracellular Matrix Degradation - page 12

moderating ADAM17/TACE activity (Mohan et al. 2002 ), and in the absence of
TIMP3, constitutive levels of TNF are elevated due to increased basal activity of

ADAM17 (Mohammed et al. 2004 ). Together, these data indicate strongly that
TIMPs do in fact inhibit metalloproteinase activity in vivo , for at least some
metalloproteinases.

a

1.5.3 TIMPs Impact on ECM

The role of TIMPs in regulating ECM remodeling in vivo is not so clear; however,
there is some in vivo evidence with Timp3 -/- mice that suggests TIMPs can impact
ECM metabolism via their ability to silence MMP activity. The absence of TIMP3
from the developing lung leads to an increase in total metalloproteinase activity and
increased fibronectin degradation, which is reversed by the addition of a synthetic
inhibitor of metalloproteinases (Gill et al. 2003 ; Gill et al. 2006 ). Furthermore,
mature lungs from Timp3 -/- mice have not only reduced fibronectin abundance, but
also decreased levels of interstitial collagen, both of which have been attributed to
enhanced metalloproteinase activity (Leco et al. 2001 ; Martin et al. 2003 ). Addi-
tionally, decreased collagen abundance is also observed in the aged hearts of
Timp3 -/- mice, and enhanced fibronectin degradation is present in the involuting
mammary glands of Timp3 -/- mice (Fata et al. 2001 ; Fedak et al. 2004 ). Collec-
tively, these data suggest that TIMP3 functions to govern normal matrix remodel-
ing and turnover.
Matrix remodeling is also a component of repair following tissue injury; how-
ever, aberrant degradation and/or deposition can result in diseases such as pulmo-
nary fibrosis, which is the result of parenchymal lung scarring due to excessive
extracellular matrix deposition (Chua et al. 2005 ). Members of both the MMP and
TIMP families have been implicated in the genesis of pulmonary fibrosis, with
TIMPs initially considered to be profibrotic and MMPs considered to attenuate
fibrosis (Cabrera et al. 2007 ; Manoury et al. 2006 ; Selman et al. 2000 ; Swiderski
et al. 1998 ). This idea arose from the generally held, though, as discussed, now
largely disputed, idea that MMPs degrade ECM, and from correlative observations
that all TIMPs are overexpressed in pulmonary fibrosis and bleomycin-injured mice
(Garcia-Alvarez et al. 2006 ; Madtes et al. 2001 ; Selman et al. 2000 ; Swiderski et al.
1998 ). However, experimental observations do not support the idea that excess
TIMPs block the ability of MMPs to resolve fibrosis. Indeed, the use of a broad-
acting metalloproteinase inhibitor or overexpression of TIMP1 resulted in
decreased fibrosis in bleomycin-treated mice (Corbel et al. 2001 ; Fattman et al.
2008 ), and in the absence of TIMP3, collagen deposition, and hence fibrosis, is
increased following bleomycin-induced injury (Gill et al. 2010a ). Furthermore,
fibrosis is enhanced following heart injury in Timp3 / mice due to increased
TGF 1 activity (Kassiri et al. 2009 ), suggesting that if TIMPs function to balance

MMP activity following injury, they may do so when the proteinases perform some
of their many non-ECM-related functions.

b