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Accelerating Wound Repair by Targeting Connexin43 Expression
with control wounds.
10
Fine blood vessels can be found ramifying faster, as there is less Cx43 to remove before migration can begin.
throughout the treated granulation tissue at times when much However, it turns out that the dynamics of connexin regulation in
thicker vessels have only just started to invade the edges of the response to injury are also abnormal in STZ-diabetic rats. Instead of
control tissue, indicating more rapid angiogenesis. These fine decreasing in response to injury, Cx43 protein levels dramatically
vessels gradually thicken to the size found in normal dermis as increase in the cells of the epidermal leading edge and re-
the scar matures. epithelialisation does not begin until all of this extra Cx43 has been
destroyed two days later, making the process much slower overall than
Cx43–asODN treatment enhances wound healing in a variety of in control rats. However, we were excited to find that treatment of STZ-
mammalian models, including incisional and excisional full-thickness diabetic rat wounds with a single application of Cx43–asODN gel was
skin and corneal wounds in mice, rats and pigs. Applied to able to prevent the initial upregulation of Cx43 in response to injury. The
partial-thickness thermal injuries of skin, it reduces the extension of treated wounds in STZ-diabetic rats were found to re-epithelialise at the
the burn from injured tissue to healthy neighbouring tissue.
14
This same rate as control wounds in non-diabetic rats.
20
clinically recognised extension of a burn normally takes place over
the first 24 hours after injury, and can cause diagnostic and Thus, it would appear that the expression of Cx43 protein in epidermal
therapeutic problems. Significant effects of the treatment on burns leading-edge cells directly inhibits their ability to crawl forwards and
are also seen in respect of the inflammatory response, with lower close the wound. This is consistent with the description by Brandner
levels of blister exudate and reduced neutrophil invasion. Together, et al.
19
of sustained high levels of Cx43 in the epidermal edge of
the reduced extension and reduced inflammation enhance the rate chronic diabetic wounds. It is also consistent with a recent report
and the quality of healing and scar formation, just as after physical from Nakano et al.,
11
who have shown that the closure of a corneal
lesions. Clearly, this approach will be a useful adjunct in managing wound is significantly delayed when Cx43 is overexpressed. Taken
partial thickness burns. together, these observations point to Cx43 as a prime target for
therapeutic intervention in diabetic wounds and chronic wounds as
Targeting Connexin43 May Have Special well as normal tissue repair.
Benefits for Diabetic Wounds
Wound healing does not always proceed normally and it is well Concluding Remarks – Where Next?
established that healing is impaired in both elderly and diabetic In general, biological processes have already been optimised by
members of the population. Chronic, ulcerated wounds are common natural selection and we tinker with them at our peril. However, it
on the lower limbs of these groups and are extremely debilitating. seems likely that in evolution, wound healing has been optimised for
Currently, there are no effective treatments for these hard-to-heal much rougher, dirtier and more dangerous conditions than those we
wounds, and they often become infected and gangrenous, thus encounter in today’s environment, assigning top priority to defence
necessitating amputation. Indeed, diabetic ulcers are the most against pathogens that may cause sepsis and death, with a much
common reason for non-traumatic amputation in the western world. lower priority to cosmetic outcome, and little or none to the needs of
Unfortunately, there are no good animal models of chronic wounds in those beyond reproductive age. Thus, real improvements should be
which to examine connexin dynamics. However, it is well known possible and many rational approaches have been proposed, some of
that wounds in diabetic mice and rats have longer repair times, less which have reached clinical trials. Although connexins are
wound contraction, slower re-epithelialisation and increased newcomers to the list of therapeutic targets, their roles in cell
thickness of granulation tissue.
15–17
There have been few studies of communication are so fundamental that they may turn out to be more
connexins in diabetic conditions, but an elevation of communication powerful than the downstream targets they control. Our patented
and Cx43 protein in diabetic fibroblasts has been reported.
18
In Cx43–asODN treatment has successfully completed second-species
addition, in human chronic diabetic wounds, a failure of Cx43 to studies in pigs and is in clinical trials in human patients. While we wait
downregulate normally in the cells of the epidermal leading edge has for the results, we shall continue to probe the cellular mechanisms
been detected.
19
through which it acts. ■
Our recent observations in streptozotocin-induced (STZ) diabetic rats
have shown that Cx43, Cx26 and Cx30 protein levels are significantly
David L Becker is a Professor of Cellular Imaging in the
Research Department of Cell and Development Biology
reduced in the intact diabetic epidermis. However, this is not part of a
at University College London (UCL), where his research
global downregulation of connexins in response to diabetes, as the
focuses on gap-junctional communication in
level of Cx43 protein is increased in the diabetic dermis.
20
Dye-transfer
development and disease. He directs the imaging unit
within UCL’s Centre for Cell and Molecular Dynamics.
studies confirm that communication is reduced in the epidermis and
With Professor Colin Green, he has developed a
elevated in the dermis, in agreement with the observations of Abdullah
patented technique for targeting connexin43 expression
et al.
18
on diabetic fibroblasts. With reduced levels of Cx43 in the
to accelerate wound healing while reducing scarring.
diabetic epidermis, one would predict that re-epithelialisation would be
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4. Richard G, Clin Exp Dermatol, 2003;28:397–409. 10. Mori R, et al., J Cell Sci, 2006;119: 5193–5203. 295–301.
5. Coutinho P, et al., Cell Biol Int, 2003;27:525–41. 11. Nakano Y, et al., Invest Ophthalmol Vis Sci, 2008;49:93–104 18. Abdullah SA, et al., Endocrine, 1999;10:35–41.
6. Common JE, et al., Biochem Biophys Res Commun, 12. Kretz M, et al., J Cell Sci, 2003;116:3443–52. 19. Brandner JM, et al., J Invest Dermatol, 2004; 122:
2002;298:651–6. 13. Martin P, et al., Curr Biol, 2003;13:1122–8. 1310–20.
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EUROPEAN DERMATOLOGY 81
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