Osteocytes, former osteoblasts entombed in the bone matrix, form an extensive cell communication network that is thought to detect microdamage and mechanical strains and to transmit signals leading to repair and compensatory bone augmentation or reduction. Bone active hormones and drugs control the integrity of this network by regulating osteocyte apoptosis, which might be a determinant of bone strength. Herein we demonstrate that mechanical stimulation by stretching activates the ERKs, which in turn are responsible for the attenuation of osteocyte apoptosis. The effect of osteocyte stretching is transmitted by integrins and cytoskeletal and catalytic molecules, such as Src kinases. Stretch-induced antiapoptosis also requires nuclear translocation of ERKs and new gene transcription. The evidence linking mechanical stimulation, activation of an integrin/cytoskeleton/Src/ERK signaling pathway, and osteocyte survival provides a mechanistic basis for the profound role of mechanical forces, or lack thereof, on skeletal health and disease.

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The accumulation of amyloid ␤ (A␤) in the walls of small vessels in the cerebral cortex is associated with diseases characterized by dementia or stroke. These include Alzheimer's disease, Down syndrome, and sporadic and hereditary cerebral amyloid angiopathies (CAAs) related to mutations within the A␤ sequence. A higher tendency of A␤ to aggregate, a defective clearance to the systemic circulation, and insufficient proteolytic removal have been proposed as mechanisms that lead to A␤ accumulation in the brain. By using immunoprecipitation and mass spectrometry, we show that insulin-degrading enzyme (IDE) from isolated human brain microvessels was capable of degrading 125 I-insulin and cleaved A␤-(1-40) wild type and the genetic variants A␤ A21G (Flemish), A␤ E22Q (Dutch), and A␤ E22K (Italian) at the predicted sites. In microvessels from Alzheimer's disease cases with CAA, IDE protein levels showed a 44% increase as determined by sandwich enzymelinked immunosorbent assay and Western blot. However, the activity of IDE upon radiolabeled insulin was significantly reduced in CAA as compared with agematched controls. These results support the notion that a defect in A␤ proteolysis by IDE contributes to the accumulation of this peptide in the cortical microvasculature. Moreover they raise the possibility that IDE inhibition or inactivation is a pathogenic mechanism that may open novel strategies for the treatment of cerebrovascular A␤ amyloidoses.Amyloid ␤ (A␤) 1 peptide deposition in the walls of small arteries and less often in venules and capillaries of the cerebral cortex is a prominent feature of several neuropathological conditions characterized by dementia or stroke. These include Alzheimer's disease (AD), Down syndrome, and sporadic and autosomal dominant cerebral amyloid angiopathies (CAAs) (Ref. 1, and for a review, see Ref.2). In sporadic AD, a large proportion of the cases show A␤-(1-40) and A␤-(1-42/43) accumulation in the media and adventitia of brain vessels. Although the contribution of such deposits to the pathophysiology of dementia is not known, their extent and localization are strongly influenced by the apoE genotype (3-5). Sporadic CAA accounts for ϳ5% of strokes, and in this condition, A␤ wild type (wt) is the main component of amyloid deposits (Ref. 6, and for a review, see Ref. 7). The Flemish (A21G), Dutch (E22Q), and Italian (E22K) genetic variants of A␤ show a remarkable tendency to accumulate in the leptomeningeal and cortical vasculature leading to fatal hemorrhagic strokes around the 5th decade of life (8 -10). In addition, the Arctic (E22G) and Iowa (D23N) variants of A␤ present clinically with dementia, and yet at the pathological level they also show prominent vascular deposits (11,12). Interestingly the Dutch, Italian, and Iowa A␤ variants, when aggregated, are capable of inducing in vitro toxicity upon endothelial and smooth muscle cells, suggesting a pathogenic relationship between A␤ deposition, vascular pathology, and clinical manifestations (10,12,13). With regard to the underlyi...