Role of ERαMISS in the Effect of Estradiol on Cancellous and Cortical Femoral Bone in Growing Female Mice

Estrogen receptor-α (ERα) acts primarily in the nucleus as a transcription factor involving two activation functions, AF1 and AF2, but it can also induce membrane-initiated steroid signaling (MISS) through the modulation of various kinase activities and/or secondary messenger levels. Previous work has demonstrated that nuclear ERα is required for the protective effect of the estrogen 17ß-estradiol (E2), whereas the selective activation of ERαMISS is sufficient to confer protection in cortical but not cancellous bone. The aim of this study was to define whether ERαMISS is necessary for the beneficial actions of chronic E2 exposure on bone. We used a mouse model in which ERα membrane localization had been abrogated due to a point mutation of the palmitoylation site of ERα (ERα-C451A). Alterations of the sex hormones in ERα-C451A precluded the interpretation of bone parameters that were thus analyzed on ovariectomized and supplemented or not with E2 (8 µg/kg/d) to circumvent this bias. We found the beneficial action of E2 on femoral bone mineral density as well as in both cortical and cancellous bone was decreased in ERα-C451A mice compared with their wild-type littermates. Histological and biochemical approaches concurred with the results from bone marrow chimeras to demonstrate that ERαMISS signaling affects the osteoblast but not the osteoclast lineage in response to E2. Thus, in contrast to the uterine and endothelial effects of E2 that are specifically mediated by nuclear ERα and ERαMISS effects, respectively, bone protection is dependent on both, underlining the exquisite tissue-specific actions and interactions of membrane and nuclear ERα.

Inherited platelet disorders and oral health.

Platelets play a key role in thrombosis and hemostasis. Accumulation of platelets at the site of vascular injury is the first step in the formation of hemostatic plugs, which play a pivotal role in preventing blood loss after injury. Platelet adhesion at sites of injury results in spreading, secretion, recruitment of additional platelets, and formation of platelet aggregates. Inherited platelet disorders are rare causes of bleeding syndromes, ranging from mild bruising to severe hemorrhage. The defects can reflect deficiency or dysfunction of platelet surface glycoproteins, granule contents, cytoskeletal proteins, platelet pro-coagulant function, and signaling pathways. For instance, Bernard-Soulier syndrome and Glanzmann thrombasthenia are attributed to deficiencies of glycoprotein Ib/IX/V and GPIIb/IIIa, respectively, and are rare but severe platelet disorders. Inherited defects that impair platelet secretion and/or signal transduction are among the most common forms of mild platelet disorders and include gray platelet syndrome, Hermansky-Pudlak syndrome, and Chediak-Higashi syndrome. When necessary, desmopressin, antifibrinolytic agents, and transfusion of platelets remain the most common treatment of inherited platelet disorders. Alternative therapies such as recombinant activated factor VII are also available for a limited number of situations. In this review, we will discuss the management of patients with inherited platelet disorders in various clinical situations related to dental cares, including surgical intervention.