Phospholipase C gamma-2 (PLCγ2)-dependent calcium (Ca 2+ ) oscillations are indispensable for nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) activation and downstream gene transcription driving osteoclastogenesis during skeletal remodeling and pathological bone loss. Here we describe, to our knowledge, the first known function of transmembrane protein 178 (Tmem178), a PLCγ2 downstream target gene, as a critical modulator of the NFATc1 axis. In surprising contrast to the osteopetrotic phenotype of PLCγ2 −/− mice, Tmem178 −/− mice are osteopenic in basal conditions and are more susceptible to inflammatory bone loss, owing to enhanced osteoclast formation. Mechanistically, Tmem178 localizes to the ER membrane and regulates RANKL-induced Ca 2+ fluxes, thus controlling NFATc1 induction. Importantly, down-regulation of Tmem178 is observed in human CD14 + monocytes exposed to plasma from systemic juvenile idiopathic arthritis patients. Similar to the mouse model, reduced Tmem178 expression in human cells correlates with excessive osteoclastogenesis. In sum, these findings identify an essential role for Tmem178 to maintain skeletal mass and limit pathological bone loss.

Precise regulation of the kinetics and magnitude of Ca2+ signaling enables this signal to mediate diverse responses, such as cell migration, differentiation, vesicular trafficking, and cell death. Here, we showed that the Ca2+-binding protein calmodulin (CaM) acted in a positive feedback loop to potentiate Ca2+ signaling downstream of the Tec kinase family member Itk. Using NMR (nuclear magnetic resonance), we mapped CaM binding to two loops adjacent to the lipid-binding pocket within the Itk pleckstrin homology (PH) domain. The Itk PH domain bound synergistically to Ca2+/CaM and the lipid phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3], such that binding to Ca2+/CaM enhanced the binding to PI(3,4,5)P3 and vice versa. Disruption of CaM binding attenuated Itk recruitment to the membrane and diminished release of Ca2+ from the endoplasmic reticulum. Moreover, disruption of this feedback loop abrogated Itk-dependent production of the proinflammatory cytokine IL-17A (interleukin-17A) by CD4+ T cells. Additionally, we found that CaM associated with PH domains from other proteins, indicating that CaM may regulate other PH domain–containing proteins.

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BackgroundEndovascular treatment of lesions associated with the cerebellar arteries is ideally performed with preservation of cerebellar artery flow, but cerebellar artery sacrifice may sometimes be necessary. Clinical outcomes and complication rates of cerebellar artery sacrifice not well defined.MethodsWe retrospectively reviewed cases of endovascular sacrifice of the superior cerebellar artery (SCA), posterior inferior cerebellar artery (PICA), and anterior inferior cerebellar artery (AICA) in patients with aneurysms, arteriovenous malformations (AVM), or tumors supplied by the corresponding artery. Baseline modified Rankin Scale (mRS) and pre-procedure acute intracranial hemorrhage hydrocephalus, and/or ventriculostomy were recorded along with diameter of the sacrificed cerebellar artery. Outcomes included new clinical neurological deficits, imaging evidence of cerebellar infarction, worsening hydrocephalus, new EVD placement, and craniectomy within 4 weeks of the procedure. Modified Rankin Scale at discharge and at 3 months was also recorded.ResultsOf the 28 patients treated with endovascular cerebellar artery sacrifice, 22 had aneurysms, 5 had AVMs, and 1 had a tumor (hemangioblastoma) fed by the sacrificed cerebellar artery. Overall, 16 PICAs, 8 SCAs, and 4 AICAs were sacrificed. The mean vessel diameter was 1.45 mm. Twelve patients (42.9%) developed clinical neurological deficits within 4 weeks of the procedure that could be attributed to the occluded vessel. Of these patients, 8 developed imaging evidence of infarction in the corresponding arterial territory within 4 weeks of the procedure. Separately, there were 3 patients that developed imaging evidence of infarction without associated clinical neurological deficits. The mean vessel diameter of patients who developed imaging evidence of infarction was 1.2 mm, and the mean vessel diameter of patients who did not develop imaging evidence of infarction was 1.5 mm. Ten patients (35.7%) developed worsening hydrocephalus within 4 weeks of the procedure; 6 of these patients required placement of a new EVD. A single patient without worsening hydrocephalus required a new EVD electively after several unsuccessful attempts at weaning the indwelling contralateral EVD. Two patients required craniotomy within 4 weeks of the procedure, one which was planned pre-procedure and the other which was for evacuation of a new acute hematoma secondary to AVM hemorrhage. Six patients (21.4%) died prior to hospital discharge. Sixteen patients (57.1%) made a good recovery at 3 months (mRS ≤2). Mean angiographic follow-up period was 137.7 days (range 0–1169 days).ConclusionsSimilar to open surgical cerebellar artery sacrifice, endovascular cerebellar artery sacrifice is associated with a high risk of infarction, hydrocephalus, and death.Patient # Age Sex Pathology treated Vessel sacrificed Diameter of sacrificed vessel (in mm) Baseline mRS Pre- ICH? Pre- hydrocephalus? Pre- EVD? Post- Neuro deficit? Post- Imaging evidence of infarct? Post- Worsening hydrocephalus? Pos...