Parathyroid Hormone Hormone-Related Protein and the PTH Receptor Regulate Angiogenesis of the Skin

Abstract

In developing organs, parathyroid hormone (PTH)/parathyroid hormone-related protein (PTHrP) receptor (PPR) signaling inhibits proliferation and differentiation of mesenchyme-derived cell types resulting in control of morphogenic events. Previous studies using PPR agonists and antagonists as well as transgenic overexpression of the PPR ligand PTHrP have suggested that this ligand receptor combination might regulate the anagen to catagen transition of the hair cycle. To further understand the precise role of PTHrP and the PPR in the hair cycle, we have evaluated hair growth in the traditional K14-PTHrP (KrP) and an inducible bitransgenic PTHrP mice. High levels of PTHrP trangene expression limited to the adult hair cycle resulted in the production of shorter hair shafts. Morphometric analysis indicated that reduced proliferation in the matrix preceded the appearance of thinner hair follicles and shafts during late anagen. CD31 staining revealed that the late anagen hair follicles of the KrP mice were surrounded by reduced numbers of smaller diameter capillaries as compared to controls. Moreover, the fetal skins of the PTHrP and PPR knockouts (KOs) had reciprocal increases in the length, diameter, and density of capillaries. Finally, crossing the KrP transgene onto a thrombospondin-1 KO background reversed the vascular changes as well as the delayed catagen exhibited by these mice. Taken together, these findings suggest that PTHrP's influence on the hair cycle is mediated in part by its effects on angiogenesis.

The Effect of Parathyroid Hormones on Hair Follicle Physiology: Implications for Treatment of Chemotherapy-Induced Alopecia

“…In accordance with the suspected influence of decreased angiogenesis on the hair follicle diameter, a 33% decrease in vessel length and vessel diameter was observed during the study with transgenic mice that overexpressed PTHrP. On the other hand, in PTHrP knockout mice (lack of PTHrP/PPR expression) increased vasculature was observed [42]. There is still a question about the pathomechanism of the regulation of angiogenesis caused by PTHrP/PPR signalling.…”

“…The PTHrP mRNA level decreases in early anagen and then peaks during late anagen, where transcripts of PTHrP are found in the outer root sheath of the non-permanent portion of the hair follicle [41]. It must be noted that the non-permanent portion of the hair follicle undergoes apoptosis during catagen [42]. On the other hand, PPR mRNA expression, which is highest during angiogenesis, is relatively low in adulthood, only increasing during early anagen in the connective tissue sheath that surrounds the growing hair follicle [41].…”

“…On the other hand, PPR mRNA expression, which is highest during angiogenesis, is relatively low in adulthood, only increasing during early anagen in the connective tissue sheath that surrounds the growing hair follicle [41]. The PTH/PTHrP signalling pathway is then, as it has already been said, the next part of the complex epithelial-mesenchymal cross-acting regulation of hair cycling [42. ]…”

“…Through investigations into the mechanisms of antiproliferative activity of PTH/PTHrP, it has been found that the N-terminal portion of PTHrP (a fragment similar to PTH) has also been reported to inhibit angiogenesis in endothelial cells in vitro when there is an overexpression of PTHrP reduced tumour vascularization in vivo [42]. The next evidence for this specific way of action of PTHrP is that premature angiogenesis is also found as a problem leading to the chondrodystrophy associated with PTHrP and PPR knockout mice [44].…”

“…As PTHrP has been proven to be a regulator of angiogenesis, the vasculature of the hair follicle in K14-PTHrP mice was, as suspected, also altered [42]. It is understandable that anagen hair units need extensive angiogenesis for their highly proliferating cells [47].…”