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Wound healing is a complex and well-orchestrated biological process. Corneal epithelial cells (CECs) must respond quickly to trauma to rapidly restore barrier function and protect the eye from noxious agents. They express a high level of ß2-adrenergic receptors but their function is unknown. Here, we report the novel finding that they form part of a regulatory network in the corneal epithelium, capable of modulating corneal epithelial wound repair. ß-adrenergic receptor agonists delay CEC migration via a protein phosphatase 2A-mediated mechanism and decrease both electric field-directed migration and corneal wound healing. Conversely, ß-adrenergic receptor antagonists accelerate CEC migration, enhance electric field-mediated directional migration, and promote corneal wound repair. We demonstrate that CECs express key enzymes required for epinephrine (ß-adrenergic receptor agonist) synthesis in the cytoplasm and can detect epinephrine in cell extracts. We propose that the mechanism for the pro-motogenic effect of the ß-adrenergic antagonist is blockade of the ß2-adrenergic receptor preventing autocrine catecholamine binding. Further investigation of this network will improve our understanding of one of the most frequently prescribed class of drugs. J. Cell. Physiol. 211: 261–272, 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Endothelialization repairs the lining of damaged vasculature and is a key process in preventing thrombosis and restenosis. It has been demonstrated that extracellular calcium ([Ca2+]o) influx is important for subsequent endothelialization. The role of intracellular Ca2+ stores in mechanical denudation induced intracellular calcium ([Ca2+]i) rise and endothelialization remains to be demonstrated. Using monolayer culture of a human endothelial cell line (human umbilical vein endothelial cell, HUVEC), we investigated [Ca2+]i wave propagation and re-endothelialization following mechanical denudation. Consistent with previous reports for other types of cells, mechanical denudation induces calcium influx, which is essential for [Ca2+]i rise and endothelialization. Moreover, we found that intracellular Ca2+ stores are also essential for denudation induced [Ca2+]i wave initiation and propagation, and the subsequent endothelialization. Thapsigargin which depletes intracellular Ca2+ stores completely abolished [Ca2+]i wave generation and endothelialization. Xestospongin C (XeC), which prevents Ca2+ release from intracellular Ca2+ stores by inhibition of inositol 1,4,5-trisphosphate (IP3) receptor, inhibited intercellular Ca2+ wave generation and endothelialization following denudation. Purinergic signaling through a suramin sensitive mechanism and gap junction communication also contribute to in intercellular Ca2+ wave propagation and re-endothelialization. We conclude that intracellular Ca2+ stores, in addition to extracellular Ca2+, are essential for intracellular Ca2+ signaling and subsequent endothelialization following mechanical denudation. J. Cell. Physiol. 214: 595–603, 2008. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Osteoclasts are multinuclear giant cells responsible for bone resorption in lytic bone diseases such as osteoporosis, arthritis, periodontitis, and bone tumors. Due to the severe side-effects caused by the currently available drugs, a continuous search for novel bone-protective therapies is essential. Artesunate (Art), the water-soluble derivative of artemisinin has been investigated owing to its anti-malarial properties. However, its effects in osteoclastogenesis have not yet been reported. In this study, Art was shown to inhibit the nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis, the mRNA expression of osteoclastic-specific genes, and resorption pit formation in a dose-dependent manner in primary bone marrow-derived macrophages cells (BMMs). Furthermore, Art markedly blocked the RANKL-induced osteoclastogenesis by attenuating the degradation of IκB and phosphorylation of NF-κB p65. Consistent with the in vitro results, Art inhibited lipopolysaccharide (LPS)-induced bone resorption by suppressing the osteoclastogenesis. Together our data demonstrated that Art inhibits RANKL-induced osteoclastogenesis by suppressing the NF-κB signaling pathway and that it is a promising agent for the treatment of osteolytic diseases. [ABSTRACT FROM AUTHOR]

Effectively directed neuron migration is critical for development and repair in the central nervous system (CNS). Endogenous electric fields (EFs) are widespread in developing and regenerating tissues and regulate a variety of cell behaviors including directed cell migration. Electrically-directed neuronal migration has not been tested previously and we show that an applied EF directs migration of hippocampal neurons toward the cathode at a field strength of 120 mV/mm, close to the physiological range. Reversal of the field polarity reversed the direction of neuron migration. Neuron migration from an explant also was directed by an applied EF. Mechanistically, EF-guided migration was transduced by activation of the second messenger molecules ROCK (Rho-associated protein kinase) and PI3 kinase (phosphoinositide-3 kinase) since their pharmacological inhibition decreased the directedness and speed of neuron migration. This work demonstrates that rat hippocampal neurons respond to applied EFs with directional migration and raises the possibility that EFs may be used as a cue to direct neuronal migration in novel strategies to repair the CNS. J. Cell. Physiol. 216: 527–535, 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]