The receptor activator of NF-B (RANKL) is the essential signal required for full osteoclast (OC) development, activation, and survival. RANKL is highly expressed in areas of trabecular bone remodeling and inflammatory bone loss, is increased on marrow stromal cells or osteoblasts by osteotropic hormones or cytokines, and is neutralized by osteoprotegerin (OPG), a soluble decoy receptor also crucial for preventing arterial calcification. Vascular endothelial cells (VEC) are critically involved in bone development and remodeling and influence OC recruitment, formation, and activity. Although OCs develop and function in close association with bone VEC and sinusoids, signals mediating their interactions are not well known. Here, we show for the first time that human microvascular endothelial cells (HMVEC) express transcripts for both RANKL and OPG; inflammatory cytokines tumor necrosis factor-␣ and interleukin-1␣ elevate RANKL and OPG expression 5-40-fold in HMVEC (with an early OPG peak that declines as RANKL rises), and RANKL protein increases on the surface of tumor necrosis factor-␣-activated HMVEC. Cytokine-activated HMVEC promoted the formation, fusion, and bone resorption of OCs formed in co-cultures with circulating human monocytic precursors via a RANKLmediated mechanism fully antagonized by exogenous OPG. Furthermore, paraffin sections of human osteoporotic fractured bone exhibited increased RANKL immunostaining in vivo on VEC located near resorbing OCs in regions undergoing active bone turnover. Therefore, cytokine-activated VEC may contribute to inflammatorymediated bone loss via regulated production of RANKL and OPG. VEC-derived OPG may also serve as an autocrine signal to inhibit blood vessel calcification.The receptor activator of NF-B ligand (RANKL), 1 also known as osteoprotegerin ligand (OPGL), osteoclast differentiation factor, or TNF-related activation-induced cytokine (TRANCE), is a recently discovered transmembrane molecule of the tumor necrosis factor (TNF) ligand superfamily that is highly expressed in lymphoid tissues and trabecular bone, particularly in areas associated with active bone remodeling or inflammatory osteolysis (1-4). RANKL is the essential and final common signal required both in vitro and in vivo for full osteoclastic (OC) differentiation from multipotential hematopoietic precursor cells into mature multinucleated bone-resorptive OCs in the presence of the permissive factor macrophage colony-stimulating factor (M-CSF) (1-7). RANKL expressed on the surface of osteoblasts (OB) or bone marrow stromal cells (BMSC) interacts with a cell surface receptor, RANK, present on pre-OC (induced by M-CSF) and mature OC to stimulate their fusion, development, bone resorption, and cell survival (5-9). RANKL expression increases during early OB development and is up-regulated in OB and BMSC by various proresorptive stimuli such as parathyroid hormone (PTH), 1,25-dihydroxyvitamin D 3 (VD 3 ), dexamethasone (Dex), prostaglandin E 2 , or interleukin-11 (IL-11) (6, 10 -12). Recently, the pro-reso...
In certain nonlinear systems, of which neurons are an example, the addition of random fluctuations, or “noise”, can enhance the detectability or transmission efficiency of a weakly applied signal. This counterintuitive statistical process, called stochastic resonance, —first advanced as a possible explanation for the observed periodic recurrences of the Earth’s ice ages [Benzi et al., 1981; Nicolis, 1993] —has by now been well established in a variety of physical systems [Wiesenfeld & Moss, 1995]. Recently it has been observed in the sensory nervous systems of two different arthropods [Douglass et al., 1994; Levin & Miller, 1996; Pei et al., preprint] and may be deeply linked to the evolution of all sensory systems. We report here the results of an experiment—the first in a human modality—designed to study the possibility of SR in the median nerve. Moreover, two additional features of this work are unique: first, our study makes use of the internal noise (as opposed to previous protocols wherein the noise was introduced externally) and second, we study the transmission of an aggregate stimulus through a bundle of individual neurons which are thought to be connected in parallel, a subject of recent theoretical [Collins et al., 1995] and experimental [Bezrukov & Vodynoy, 1995] interest. In our experiment, near subthreshold electrical stimuli were applied periodically to the median nerve, and responses were detected and signal averaged by electromyography. The internal noise intensity was mediated by muscle tension. The results are consistent with the hypothesis that internally generated electrical noise can enhance the signal transmission efficiency in this modality.
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