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Wound Management
Accelerating Wound Repair by Targeting Connexin43 Expression
David L Becker
Professor, Cellular Imaging, Research Department of Cell and Developmental Biology, University College London
Abstract
Gap-junction proteins, the connexins, are dynamically regulated at a wound site during the healing process as different communication
properties are required for specific events. For instance, in the keratinocytes at the edge of the wound connexin43 (Cx43) is downregulated
and replaced with Cx26 and Cx30 as the cells become migratory and crawl forwards to close the wound. We have found that speeding up
the downregulation of Cx43 at a wound site with the topical application of a Cx43 antisense gel significantly accelerates the healing process,
while reducing inflammation and scar formation in a variety of wound types. Interestingly, in animals with diabetes, where wound healing is
notoriously slow, Cx43 fails to downregulate at the wound edge and instead its expression is elevated. Preventing this upregulation in
diabetic wounds via the Cx43 antisense gel restores the rate of healing to normal or better. There are clear therapeutic benefits to be gained
from using antisense technology in wound healing, and it is now undergoing clinical trials in a variety of different wound types.
Keywords
Gap junction, connexin, Cx43, Cx26, Cx30, wound healing, tissue repair, diabetes, antisense
Disclosure: This work has been supported by grants from the Wellcome Trust, the Biotechnology and Biological Sciences Research Council (BBSRC) and the Association of
Medical Research Charities (AMRC). The author has no conflicts of interest to declare.
Received: 16 June 2008 Accepted: 17 July 2008
Correspondence: David L Becker, Professor of Cellular Imaging, Department of Cell and Developmental Biology, University College London, Gower Street, London,
d.becker@ucl.ac.uk
It comes as no surprise that a process as complex as the healing of a connexin proteins, including Cx43, Cx30, Cx26, Cx31 and Cx31.1.
2–4
wound requires extensive communication between the participating However, Cx43 is the most ubiquitous, having been localised in the
cells. Several established extracellular mediators are known to be cutaneous vasculature, fibroblasts, dermal appendages and
involved, including cytokines and growth factors. However, this article keratinocytes.
2,5
Gap junctions are evidently important in maintaining
focuses primarily on gap-junction channels, which respond early to homeostasis in the skin, because point mutations in Cx26, Cx30 and
wounding and uniquely allow direct intracellular communication Cx31 underlie syndromic and non-syndromic skin diseases, including
between the cytoplasmic compartments of neighbouring cells, keratitis–ichthyosis–deafness (KID) syndrome, hystrix-like ichthyosis
bypassing the extracellular space. with deafness (HID), Vohwinkel syndrome and erythrokeratoderma
variabilis (EKV).
4,6,7
Gap Junctions in the Skin Respond
Dynamically to Wounding Following wounding of the mammalian epidermis, the expression of
Although gap junctions are a relatively novel concept in wound connexin proteins is tightly regulated at both transcriptional and
healing, they have long been implicated in the control of many of its translational levels, and a stereotyped sequence of dynamic changes
component cellular processes, such as proliferation, migration, correlates with specific events during wound closure.
5,8
Cx43 and
adhesion and inflammation.
1
A gap-junction channel between two Cx31.1 start to be downregulated in the keratinocytes of the wound
cells is formed by the docking of two roughly cylindrical half- edge within six hours and are hard to detect by 24–48 hours.
5,8
channels called connexons, one spanning the membrane of each Conversely, Cx26 and Cx30 are upregulated in the same leading-edge
cell. A connexon has a gated central pore that passes molecules of cells as they transform into a migratory phenotype and use
up to about 1kDa, including common intracellular second lamellipodia to crawl forwards and close the wound. Once the wound
messengers such as calcium and inositol 1,4,5-trisphosphate (InsP3). is closed, Cx26 and Cx30 downregulate towards normal levels within
Undocked connexons can also function independently as release the epidermis. Cx43 and Cx31.1
1
expression then returns as the
pathways for paracrine extracellular signals, such as adenosine epidermis regains its characteristic laminar architecture.
triphosphate (ATP). Each connexon consists of a ring of six protein
subunits called connexins, which belong to a protein family encoded Targeting Connexin43 Expression
by at least 21 genes. Family members are most commonly named Improves the Healing Process
according to their molecular weight, i.e. connexin43 (Cx43) being It has been shown that tissue repair in both the skin and the
43kDa. In the skin, gap junctions are formed from a variety of cornea is significantly enhanced if the natural downregulation of
© TOUCH BRIEFINGS 2009 79
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