GHRH and wound healing

Abstract

The principal action of growth hormone – releasing hormone (GHRH) is considered to be the stimulation of GH production and release in the pituitary¹. With the recent identification of wound –associated fibroblasts as a direct target of GHRH², this neuropeptide emerges as a rather pleiotropic hormone implicated in the regulation of various physiological and pathological processes and affecting diverse cell types.

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Besides its involvement in wound healing, GHRH has been associated with cardiac repair by acting directly upon the cardiomyocytes and promoting their survival after myocardial infarction.3,4 Mesenchymal cells are not the only cells that are responsive to GHRH since in pancreatic islet cells it induces cell proliferation and reduces apoptosis.5 The stimulation of dermal wound healing by acting, at least in part, upon the skin-associated fibroblasts,6 taken together with previous reports on the ability of GHRH to modulate the activity of telomerase in cancer cells7 (of epithelial origin) are suggestive of a wider role for GHRH in conditions involving tissue regeneration and repair. These findings raise the possibility that the potential involvement of GHRH in aging is not limited to the regulation of GH and subsequent IGF-1 levels but affects aging at the level of the whole organism.8 It may also interfere directly with the regulation of cellular and tissue aging through modulation of the tissue's regenerative potential. The latter is due to the fact that GHRH affects fibroblast proliferation as well as their migration and expression of α-smooth muscle actin (α-SMA).2 This smooth muscle actin isoform is organized into stress fibers and exerts contractile forces on the extracellular matrix.9 Thus, it appears that GHRH can regulate, simultaneously, both the kinetic profile and the differentiation of fibroblasts into myofibroblasts. This is not the first example of GHRH regulating differentiation in non-pituitary tissues. Earlier studies have demonstrated that GHRH in females promotes follicular maturation10 while in Leydig cells in the male it contributes to the regulation of the process of spermatogenesis.11

Two immediate implications of these findings can be predicted. First, native GHRH as well as its agonistic analogs may provide tools for therapeutic intervention in conditions in which tissue repair is needed. Second, it identifies an experimental system in which the physiological effects of GHRH in a peripheral tissue can be studied experimentally and pre-therapeutically.

It should be noted that the precise physiologic and biochemical mechanisms by which GHRH use leads to the finding that GHRH accelerates wound healing remains unclear. Notwithstanding the fact that it presents an opportunity for therapeutic intervention in pathophysiologic circumstances, that this mechanism as such, is indeed operational during normal wound healing remains to be established. Since the location of production of biologically active GHRH in dermal wounds remains elusive, whether endogenous GHRH produced in situ is implicated physiologically in the healing of cutaneous wounds has to be confirmed. It is conceivable that even the systemically circulating GHRH produced in the hypothalamus may reach adequate levels to contribute to this process. Another possibility is that other peptides that are structurally related to GHRH, are produced in dermal wounds during healing and it is their activity that GHRH and its agonistic analog mimic in this experimental system. This argument might be supported by the observation that GHRH and the agonistic analog utilized in this study, while they exhibit activities differing about 71.4 fold in the in vivo GH-release assay12 that targets pituitary GHRH receptor, they displayed only marginal differences in the wound healing model.1 Thus, the involvement of other receptor(s) transducing the wound healing signal is possible, and these in turn may exhibit higher affinity for peptides other than GHRH.

Whether this apparently novel function of GHRH is operational under normal conditions or it is indicative of the activity of a structurally related peptide(s) should be explored more extensively in order to elucidate some of the basic aspects of skin biology and repair as well as in view of its potential implications in therapeutic wound healing.

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