Effect of parathyroid hormone‐related protein on fibroblast proliferation and collagen metabolism in human skin

Maioli, Emanuela; Fortino, Vittoria; Torricelli, Claudia; Arezzini, Beatrice; Gardi, Concetta

doi:10.1034/j.1600-0625.2002.110403.x

Cited by 25 publications

(22 citation statements)

References 41 publications

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“…PTHrP: The PTHrP inhibits proliferation of dermal fibroblasts in a dose dependent manner, whereas a dose-dependent stimulation of cAMP, released by fibroblasts, can be concomitantly observed 57 . In contrast, PTHrP has no effect on collagen synthesis, whereas it increases metalloproteinase 2 activity.…”

Section: Biological Activity Of Hormones In Human Skinmentioning

confidence: 99%

The human skin as a hormone target and an endocrine gland

Zouboulis¹

2004

160

116

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Hormones influence the development and function of human skin which also produces and releases hormones. Recently attention has been focused on identifying and understanding the complex endocrine properties of human skin, such as expression and function of specific hormone receptors, synthesis of hormones from major classes of compounds used by the body for general purposes, organized metabolism, activation, inactivation and elimination of the hormones in specialized cells of the tissue, exertion of biological activity and release of tissue hormones in the circulation. Specifically, hormones exert their biological effects on the skin through interaction with high-affinity receptors, such as several receptors for peptide hormones and neurotransmitters, steroid and thyroid hormones. Hormones exhibit a wide range of biological activities on the skin with distinct effects caused by growth hormone/insulin-like growth factor-I, neuropeptides, sex steroids, glucocorticoids, retinoids, vitamin D, peroxisome proliferator-activated receptor ligands, eicosanoids, melatonin and serotonin. Human skin produces, activates or inactivates metabolically numerous hormones which are probably important for skin functions but also for functions of the entire human organism, such as sex hormones, especially in aged individuals, insulin-like growth factor and -binding proteins, neuropeptides, prolactin, catecholamines, retinoids, steroids, vitamin D and eicosanoids. These functions are undertaken in most cases by different skin cell populations in a coordinated way, indicating the endocrine autonomy of the skin. Characteristic examples are the metabolic pathways of the corticotropin-releasing hormone/propiomelanocortin axis, steroidogenesis, vitamin D and retinoids. The human skin is, thus, the largest, peripheral endocrine organ.

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Section: Biological Activity Of Hormones In Human Skinmentioning

confidence: 99%

The human skin as a hormone target and an endocrine gland

Zouboulis¹

2004

160

116

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“…ADRP is necessary for the trafficking of substrate for surfactant production (43), and leptin stimulates the differentiation of the alveolar type II cell (50). PTHrP affects the cellular composition of the alveolar interstitium in at least three ways: 1) it inhibits fibroblast growth (28) and stimulates apoptosis (36), causing septal thinning, 2) stimulation of epithelial type II cell differentiation by leptin (50) can inhibit epithelial cell growth (36), and 3) leptin may upregulate type IV collagen synthesis (60), reinforcing the alveolar wall (24).…”

Section: Ontogeny and Homeostasismentioning

confidence: 99%

The evolutionary continuum from lung development to homeostasis and repair

Torday¹,

Rehan²

2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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Torday JS, Rehan VK. The evolutionary continuum from lung development to homeostasis and repair. Am J Physiol Lung Cell Mol Physiol 292: L608-L611, 2007. First published November 3, 2006; doi:10.1152/ajplung.00379.2006.-A functional, developmental, and comparative biological approach is probably the most effective way for arranging gene regulatory networks (GRNs) in their biological contexts. Evolutionary developmental biology allows comparison of GRNs during development across phyla. For lung evolution, the parathyroid hormone-related protein (PTHrP) GRN exemplifies a continuum from ontogeny to phylogeny, homeostasis, and repair. PTHrP signaling between the lung endoderm and mesoderm stimulates lipofibroblast differentiation by downregulating the myofibroblast Wnt signaling pathway and upregulating the protein kinase A-dependent cAMP signaling pathway, inducing the lipofibroblast phenotype. Leptin secreted by the lipofibroblast, in turn, binds to its receptor on the alveolar type II cell, stimulating surfactant synthesis to ensure alveolar homeostasis. Failure of the PTHrP/PTHrP receptor signaling mechanism causes transdifferentiation of lipofibroblasts to myofibroblasts, which are the hallmark for lung fibrosis. We have shown that by targeting peroxisome proliferator-activated receptor ␥, the downstream target for lipofibroblast PTHrP signaling, we can prevent lung fibrosis. We speculate that the recapitulation of the myofibroblast phenotype during transdifferentiation is consistent with lung injury as lung evolution in reverse. Repair recapitulates ontogeny because it is programmed to express the cross talk between epithelium and mesoderm through evolution. This model demonstrates how epithelial-mesenchymal cross talk, when seen as a recapitulation of ontogeny and phylogeny (in both a forward and reverse direction), predicts novel, effective diagnostic and therapeutic targets.Evo-Devo; alveoli; parathyroid hormone-related protein; peroxisome proliferator-activated receptor ␥; Wnt PUBLICATION OF THE HUMAN GENOME has ushered in the "Golden Age" of biomedical research. But we lack an effective algorithm for arranging gene regulatory networks in a biological context (35), one which, like the periodic table of the elements, would predict the functions of genes, unlike interactomes that merely annotate gene and protein associations. Contemporary biology mirrors what happened in physics at the turn of the 20th century. We now have the genetic "elements" of the periodic table, and the Cambrian Burst is analogous to the Big Bang, so we should now consider the "initial conditions" for lung evolution and the "continuing strategy" for surviving the Permian extinction rather than continuing to reason backwards from phenotypes to genes (42). But we don't have the biological analog of quantum mechanics. Statistical analysis of complex genomic databases, i.e., Systems Biology, will not achieve that goal because evolution did not occur by chance. Therefore, a functional genomic approach would seem like the most effective wa...

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“…Evidence for such a role is also confirmed by studies with PTHrP knockout mice that, in addition to chondrodystrophy, displayed several cutaneous abnormalities, including a fibrotic dermis [15]. These data are linked to pathophysiological events such as wound healing, skin aging and tumor progression in which either PTHrP, cell proliferation or MMP activity are implicated [14].…”

Section: Discussionmentioning

confidence: 77%

“…Recent studies in our laboratory have demonstrated the role of PTHrP in modulating cell proliferation and extracellular matrix turnover (MMP2) in primary skin fibroblasts obtained from a single human donor [14]. Evidence for such a role is also confirmed by studies with PTHrP knockout mice that, in addition to chondrodystrophy, displayed several cutaneous abnormalities, including a fibrotic dermis [15].…”

Section: Discussionmentioning

confidence: 88%

“…We recently found that synthetic PTHrP 1 -40 strongly affects human skin fibroblast proliferation, by inhibiting 2166 V. Fortino et al PTHrP transduction pathways in fibroblasts [ 3 H]-thymidine incorporation into DNA, dose dependently. This inhibitory effect was apparently mediated by the cAMP/PKA second-messenger pathway, since an inverse correlation was found between proliferation rate and extracellular cAMP release [14].…”

mentioning

confidence: 98%

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ERKs are the point of divergence of PKA and PKC activation by PTHrP in human skin fibroblasts

Fortino¹,

Torricelli²,

Gardi³

et al. 2002

Cellular and Molecular Life Sciences (CMLS)

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Parathyroid hormone-related peptide (PTHrP) receptors, coupled to trimeric G proteins, operate in most target cells through at least three different transduction routes: Galpha s-mediated stimulation of adenylylcyclase (AC), Galpha q-mediated activation of phospholipase Cbeta (PLC) and mitogen-activated protein kinase (MAPK) activation. In this study we investigated the relative role of different pathways in human skin fibroblast proliferation. Using chemical inhibitors and activators of signal transduction, we demonstrated that: (i) AC/cAMP and PLC/1,4,5 inositol triphosphate/diacylglycerol second-messenger systems are simultaneously activated following PTHrP binding to its receptors; (ii) the mitogenic response to PTHrP derives from a balance between two counteracting pathways--an activating route mediated by protein kinase C (PKC) and an inhibitory route mediated by protein kinase A (PKA); (iii) PTHrP mitogenic effects are largely dependent on MAPKs, whose activity can be modulated by both PKA and PKC. Our results indicate that MAPKs are common targets of both transduction routes and, at the same time, their point of divergence in mediating PTHrP dual and opposite mitogenic effects.

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Effect of parathyroid hormone‐related protein on fibroblast proliferation and collagen metabolism in human skin

Cited by 25 publications

References 41 publications

The human skin as a hormone target and an endocrine gland

The human skin as a hormone target and an endocrine gland

The evolutionary continuum from lung development to homeostasis and repair

ERKs are the point of divergence of PKA and PKC activation by PTHrP in human skin fibroblasts

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