Hoxb13knockout adult skin exhibits high levels of hyaluronan and enhanced wound healing

Abstract

In contrast to adult cutaneous wound repair, early gestational fetal cutaneous wounds heal by a process of regeneration, resulting in little or no scarring. Previous studies indicate that down-regulation of HoxB13, a member of the highly conserved family of Hox transcription factors, occurs during fetal scarless wound healing. No down-regulation was noted in adult wounds. Here, we evaluate healing of adult cutaneous wounds in Hoxb13 knockout (KO) mice, hypothesizing that loss of Hoxb13 in adult skin should result in enhanced wound healing. Tensiometry was used to measure the tensile strength of incisional wounds over a 60-day time course; overall, Hoxb13 KO wounds are significantly stronger than wild-type (WT). Histological evaluation of incisional wounds shows that 7-day-old Hoxb13 KO wounds are significantly smaller and that 60-day-old Hoxb13 KO wounds exhibit a more normal collagen architecture compared with WT wounds. We also find that excisional wounds close at a faster rate in Hoxb13 KO mice. Biochemical and histochemical analyses show that Hoxb13 KO skin contains significantly elevated levels of hyaluronan. Because higher levels of hyaluronan and enhanced wound healing are characteristics of fetal skin, we conclude that loss of Hoxb13 produces a more "fetal-like" state in adult skin.

Identification and Analysis of the Promoter Region of the Human Hyaluronan Synthase 2 Gene

“…HA has been implicated in chondrogenesis and cartilage homeostasis, embryonic development, immunomodulation, wound healing, and a variety of disease processes, including arthritis, malignancies, and pulmonary and vascular disease, together with other immune and inflammatory disorders (27)(28)(29)(30)(31)(32)(33)(34)(35). In addition, the transcriptional regulation of HAS2 has potential significance in renal fibrosis (10 -12), diabetic nephropathy (13), and peritoneal inflammation (16).…”

Role of Glycosaminoglycans in Cellular Communication

“…Wounds in a fetus or newborn, expressing neonatal carbohydrate antigens, heal faster than those in adult animals in the absence of scarring, and GAG content and structure appears to play a role. 48 GAGs, such as heparin, have been used in the treatment of wounds including ulcers, stroke, diseased heart muscle, and atherogenesis. 47 Despite a fear of bleeding associated with the use of heparin in wound healing applications, it appears that the anticoagulant activity is separable from wound healing activity.…”

Proliferation and cornification during development of the mammalian epidermis

“…In support of this hypothesis, we and others have shown that Hoxb13, which is first expressed in E13.5 epidermis, is upregulated in keratinocytes that have been induced to differentiate (Komuves et al, 2003;Mack et al, 2005). Hoxb13 knockout epidermis shows significantly higher levels of hyaluronan (Mack et al, 2003), a molecule that is thought to promote cellular proliferation and inhibit differentiation (reviewed in Spicer and Tien, 2004). In addition, forced expression of Hoxb13 in a rat epidermal organotypic model significantly reduces the number of proliferating cells in the basal layer and drives terminal differentiation, as evidenced by a dramatically thickened cornified layer (Fig.…”

“…No interfollicular skin phenotype has been reported in mice that are deficient for a single Hox gene. We did, however, report that loss of Hoxb13 in skin results in the reduced expression of several epidermal differentiation markers, which is highly suggestive for definitive roles for this class of genes in skin (Mack et al, 2003). The generation of skin-specific overexpressing transgenics, multiple knockout lines within or between certain paralogous groups, and the continued identification of target genes should help to elucidate Hox function in epidermal growth and differentiation.…”

“…HOXB4, for example, is expressed in hyperproliferative diseases of the epidermis, including psoriasis, eczema, and skin cancer (Komuves et al, 2002). Hoxb13 is a prodifferentiating and antiproliferative factor (Economides et al, 2003;Mack et al, 2005); reduction in Hoxb13 expression is associated with enhanced proliferation and fetal scarless wound healing (Mack et al, 2003;Stelnicki et al, 1998a). Many interesting relationships between cutaneous syndromes and disease states and the molecules that regulate epidermal proliferation/cornification remain to be explored.…”