Intermittent PTH administration increases bone turnover, resulting in net anabolic effects on bone. These effects are primarily mediated by intracellular cAMP signaling. However, the molecular mechanisms that regulate PTH activity in bone remain incompletely understood. beta-Arrestin2, a G protein-coupled receptor regulatory protein, inhibits PTH-stimulated cAMP accumulation in vitro. Using beta-arrestin2(-/-) (KO) and wild-type (WT) mice, we investigated the response to PTH in primary osteoblasts (POB) and the effects of intermittent PTH administration on bone mass and microarchitecture in vivo. Compared with that in WT mice, PTH-stimulated intracellular cAMP was increased and sustained in KO POB. Intermittent exposure of POB to PTH significantly decreased the ratio of osteoprotegerin (OPG) receptor activator of nuclear factor-kappaB ligand (RANKL) mRNA expression in KO POB, whereas it increased this ratio in WT POB. Total body bone mass and cortical and trabecular bone parameters were 5-10% lower in male KO mice compared with WT, and these differences were magnified upon in vivo administration of intermittent PTH (80 mug/kg.d) for 1 month. Thus, PTH significantly increased total body bone mineral content as well as vertebral trabecular bone volume and thickness in WT, but not KO mice. The anabolic response to PTH in cortical bone was also slightly more pronounced in WT than KO mice. Histomorphometry indicated that PTH prominently stimulated indexes of bone formation in both WT and KO mice, whereas it significantly increased indexes of bone resorption (i.e. osteoclast number and surface) in KO mice only. In conclusion, these results suggest that beta-arrestins may specify the activity of intermittent PTH on the skeleton by limiting PTH-induced osteoclastogenesis.
Cytoplasmic arrestins regulate PTH signaling in vitro. We show that female -arrestin2 −/− mice have decreased bone mass and altered bone architecture. The effects of intermittent PTH administration on bone microarchitecture differed in -arrestin2 −/− and wildtype mice. These data indicate that arrestinmediated regulation of intracellular signaling contributes to the differential effects of PTH at endosteal and periosteal bone surfaces.Introduction: The effects of PTH differ at endosteal and periosteal surfaces, suggesting that PTH activity in these compartments may depend on some yet unidentified mechanism(s) of regulation. The action of PTH in bone is mediated primarily by intracellular cAMP, and the cytoplasmic molecule -arrestin2 plays a central role in this signaling regulation. Thus, we hypothesized that arrestins would modulate the effects of PTH on bone in vivo. Materials and Methods: We used pDXA, CT, histomorphometry, and serum markers of bone turnover to assess the skeletal response to intermittent PTH (0, 20, 40, or 80 g/kg/day) in adult female mice null for -arrestin2 (-arr2
Cutaneous T-cell lymphomas (CTCLs) are malignancies of T cells that have a special affinity for the skin. We have previously reported that much of the T-cell receptor repertoire is altered in CTCL, and both malignant and nonmalignant clones are numerically expanded, presumably in response to T-cell trophic cytokines. We therefore examined levels of the T-cell trophic cytokines IL-2, IL-4, IL-7, IL-12, IL-13, and IL-15 in plasma in 93 CTCL patients and healthy controls. Only IL-7 levels were elevated in CTCL. We next looked at lesional skin from patients with CTCL and found elevated levels of IL-7 mRNA. Explant cultures of normal and lesional CTCL skin biopsies revealed significantly more IL-7 protein production in CTCL skin. Additionally, cultures of CTCL skin released greater numbers of T cells than normal skin; this was blocked by the addition of an IL-7 neutralizing antibody. Finally, these cultures induced proliferation of normal peripheral skinhoming T cells that were added to the cultures. These observations led us to postulate that IL-7 produced by skin cells contributes to the survival and proliferation of T cells within skin lesions and is likely the source of elevated circulating IL-7 in CTCL.
IntroductionCutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of lymphoproliferative disorders of the skin 1 and are regarded as a subset of extranodal non-Hodgkin T-cell lymphomas of skinhoming memory T cells. 2 Among CTCL patients with peripheral blood involvement, there are greater numbers of T cells expressing the skin-homing cutaneous lymphocyte antigen (CLA) and the chemokine receptor CCR4 than are present in healthy donors. 3 Furthermore, the CCR4 ligand CCL17 is highly expressed on the endothelial cells in CTCL skin lesions. 3 These findings, together with the increased expression of E selectin and ICAM-1 in CTCL lesions, 4,5 suggest that the appropriate microenvironment exists for the entry of skin-homing T cells into CTCL lesions. 3 These malignant T cells may be found singly or collectively within the epidermis and admixed with an infiltrate of mononuclear cells within the papillary dermis underlying the involved epidermis.We recently reported that in all cases of advanced CTCL, and many cases of early disease, there is a significant disruption of the diversity of the T-cell repertoire in peripheral blood. 6 T-cell receptor beta-variable (BV) spectratyping revealed diminished complexity in many BV families, 6 and this correlated with diminished T-cell receptor excision circle (TREC) levels. 7 Both observations are consistent with the idea that some normal T cells are being removed from circulation and other T cells are proliferating to fill the space that this removal creates in the T-cell compartment. The idea that there may be a proliferative stimulus in the peripheral blood of CTCL patients led us to examine peripheral blood plasma for the presence of T-cell trophic cytokines Patients and healthy controls were studied, and plasma levels of interleukin-2 (IL-2), IL-4, IL-7, IL-12, IL-13, ...
PHACE syndrome represents the association of large infantile hemangiomas of the head and neck with brain, cerebrovascular, cardiac, ocular, and ventral/midline defects. Cardiac and cerebrovascular anomalies are the most common extracutaneous features of PHACE, and they also constitute the greatest source of potential morbidity. Congenital heart disease in PHACE is incompletely described, and this study was conducted to better characterize its features. This study of the International PHACE Syndrome Registry represents the largest central review of clinical, radiology, and pathology data for cardiovascular anomalies in PHACE patients to date. 62/150 (41%) subjects had intracardiac, aortic arch, or brachiocephalic vessel anomalies. Aberrant origin of a subclavian artery was the most common cardiovascular anomaly (present in 31/150 (21%) of subjects). Coarctation was the second most common anomaly, identified in 28/150 (19%), and can be missed clinically in PHACE patients because of the frequent association of arch obstruction with aberrant subclavian origin. 23/62 (37%) subjects with cardiovascular anomalies required procedural intervention. A higher percentage of hemangiomas were located on the left side of the head/neck in patients with coarctation (46% vs. 39%); however, hemangioma distribution did not predict the presence of cardiovascular anomalies overall. In conclusion, PHACE is associated with a high risk of congenital heart disease. Cardiac and aortic arch imaging with detailed assessment of arch patency and brachiocephalic origins is essential for any patient suspected of having PHACE. Longitudinal investigation is needed to determine the long-term outcomes of cardiovascular anomalies in PHACE.
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