Proteolytic cleavage of constitutively expressed proteins can generate peptides with novel bioactive properties. Matrix metalloproteinase (MMP)-2 cleaves the 4 amino-terminal residues of the chemokine, stromal cell-derived factor (SDF)-1␣, yielding a highly neurotoxic molecule, SDF(5-67), which fails to bind to its cognate receptor, CXCR4. Herein, we detected SDF(5-67) in brain monocytoid cells of HIV-infected persons, particularly in those with HIV-associated dementia. SDF(5-67) activated cell type-specific expression of proinflammatory genes including IL-1␤, TNF␣, indoleamine 2,3-dioxygenase (IDO), and IL-10 in both astrocytic and monocytoid cells (P < 0.05). Unlike SDF-1␣, SDF(5-67) caused neuronal membrane perturbations with ensuing neurotoxicity and apoptosis (P < 0.05) through engagement of an inducible receptor. CXCR3 antagonists and siRNA-mediated knockdown of CXCR3 inhibited SDF(5-67)-stimulated neurophysiological changes, neuronal death, and neuroimmune activation (P < 0.05). Moreover SDF(5-67) bound directly to CXCR3 in a competitive manner, mediated by its amino terminus. In vivo neuroinflammation, neuronal loss, and neurobehavioral abnormalities caused by SDF(5-67) (P < 0.05) were prevented by a CXCR3 antagonist. These studies reveal additive neuropathogenic properties exerted by a proteolytically cleaved chemokine as consequences of a change in receptor specificity, culminating in neurodegeneration.apoptosis ͉ chemokine ͉ human immunodeficiency virus ͉ neuron ͉ stromal cell-derived factor-1␣

Summary. The effects of bPTH-(1-84), bPTH-(1-34), bPTH-(I-34) amide (NTA 1-347 desamino bPTH-(1-34), bPTH-(2-34), bPTH-(3-34), and bPTH-(3-34) amide were tested in cultured bone cells, isolated from the osteoblast layers of fetal chicken calvaria (cyclic AMP) and in fetal rat calvaria (cyclic AMP, Ca release, and lactate production). Only bPTH-(1-84), bPTH-(1-34), and NTA 1-34 increased cyclic AMP production in a doserelated manner, both in calvaria and in bone cells, whereas all fragments (except NTA 3-34) stimulated bone resorption, the order of decreasing potency being bPTH-(1-84), NTA 1-34, bPTH-(I-34), desamino bPTH-(1-34), bPTH-(2-34), bPTH-(3-34). As in human cells, the antagonist NTA 3-34 inhibited specifically and in a dose-dependent way the cyclic AMP response of maximal concentrations of both bPTH-(1-84) and bPTH-(I-34) in rat calvaria and in chicken bone cells, when measured after short (15 min) and longer (1 89 h) incubation periods. In addition, measured after 4 h of incubation, NTA 3-34 completely inhibited bPTH-(l-84)-stimulated Ca release using maximal and submaximal concentrations. However, after 6-24 h of incubation, NTA 3-34 had no effect on bPTH-(1-84)-stimulated Ca and lactate release, even at an antagonist/agonist ratio up to 12.5 M, perhaps due to its lower affinity for the PTH receptor. From these findings we propose that (a) in bone there are two types of receptors, one governing demineralization via regulation of the calcium influx and one governing adenylate cyclase activity, and (b) the reSemi offprint requests to M. P. M. Herrmann-Erlee at the above address.J The following aggreviations are used: bPTH, bovine parathyroid hormone; NTA 1-34, ceptors are different from each other with respect to their affinities toward the agonists and the antagonist. Key words: PTH--PTH inhibitor--Cyclic AMP--Bone resorption.It is well known that bone cell metabolism is regulated by a variety of hormones such as PTH, calcitonin, the prostaglandins, 1,25-dihydroxycholecalciferol, and epinephrine. With the exception of 1,25(OH)2D~, all these agonists increase the level of cyclic AMP in the target cells. Cyclic AMPstimulating activity has also been found for a number of analogues of the 84-residue bovine parathyroid hormone molecule [1][2][3][4][5]. A synthetic fragment of the hormone, shortened at the NH._, terminus by only one amino acid [bPTH-(2-34)], does not stimulate renal adenylate cyclase activity, but was found to remain active in the in vivo chick hypercalcemia test [1].An even more striking discrepancy between the adenyl cyclase-stimulating activity and the capacity to resorb bone was found for the desamino bPTH-(1-34) [2]. However, a fragment of the hormone, shortened at the NH2 terminus by two amino acids ], does not stimulate adenylate activity in vitro nor increase hypercalcemia in vivo, but presumably binds to the hormone receptor, since it inhibits bPTH-(1-84)-stimulated renal cortical cell adenylate cyclase activity [5]. The newly synthesized analogue bPTH-(3-34) amide also lacks a...