Corticotropin-releasing hormone induces skin vascular permeability through a neurotensin-dependent process

Many skin disorders are associated with increased numbers of activated mast cells and are worsened by stress; however, the mechanism underlying these processes is not understood. Corticotropin-releasing hormone (CRH) is secreted under stress from the hypothalamus, but also in the skin, where it induces mast cell activation and vascular permeability. We investigated the effect of CRH in a number of animal models by using i.v. Evans blue extravasation as a marker of vascular permeability. Intradermal CRH is among the most potent peptides at 100 nM, its effect being nearly comparable to that of neurotensin (NT). Pretreatment of skin injection sites with the NT receptor antagonist SR48692 blocks CRH-induced vascular permeability, which is diminished in NT−/− mice, implying that NT is necessary for the effect of CRH. CRH and NT precursor mRNA are shown to be expressed in both dorsal root ganglia and skin, whereas the latter also expresses mRNA for prohormone convertase 5, an enzyme that cleaves pro-NT into its active form. We also show that the effect of both CRH and NT is absent in W/W(v) mast cell-deficient mice; however, only a fraction of skin mast cells express CRH receptors, as shown by FACS analysis of CRH receptor (CRHR) and c-kit double-positive disaggregated mouse skin mast cells. These findings suggest that CRH induces skin vascular permeability through NT acting on mast cells and that both peptides should be considered in the pathogenesis of skin disorders exacerbated by stress

Prevalence, pathogenesis, and treatment options for mastocytosis-related osteoporosis

Mastocytosis is a rare condition characterized by abnormal mast cell proliferation and a broad spectrum of manifestations, including various organs and tissues. Osteoporosis is one of the most frequent manifestations of systemic mastocytosis, particularly in adults. Osteoporosis secondary to systemic mastocytosis is a cause of unexplained low bone mineral density that should be investigated when accompanied by suspicious clinical elements. Bone involvement is often complicated by a high recurrence of fragility fractures, mainly vertebral, leading to severe disability. The mechanism of bone loss is the result of different pathways, not yet fully discovered. The main actor is the osteoclast with a relative or absolute predominance of bone resorption. Among the stimuli that drive osteoclast activity, the most important one seems to be the RANK-RANKL signaling, but also histamine and other cytokines play a significant role in the process. The central role of osteoclasts made bisphosphonates, as anti-resorptive drugs, the most rational treatment for bone involvement in systemic mastocytosis. There are a few small studies supporting this approach, with large heterogeneity of drug and administration scheme. Currently, zoledronate has the best evidence in terms of gain in bone mineral density and bone turnover suppression, two surrogate markers of anti-fracture efficacy