Effect of exogenous neurotrophins on Trk receptorphosphorylation, cell proliferation, and neurotrophin secretion by cellsisolated from the human lamina cribrosa

[摘要] Purpose: Glaucoma is the number one cause of preventable blindnessin the United States. The lamina cribrosa (LC) region of the optic nervehead (ONH) is a major site of injury in glaucomatous optic neuropathy.Neurotrophins (NTs), which include NGF, BDNF, NT-3, and NT-4, are growthfactors involved in the development and support of neurons and innon-neuronal interactions. Cells within the human LC express highaffinity tyrosine kinase receptors (Trks) for NTs. The purpose of thisstudy was to determine if exogenous NTs cause (a) phosphorylation of Trkreceptors in LC cells and ONH astrocytes and (b) cell proliferationand/or secretion of NTs by LC cells and ONH astrocytes.Methods: Trk phosphorylation in response to exogenous NGF, BDNF,NT-3, and NT-4 treatment was studied in LC cells and ONH astrocytesusing immunoprecipitation and Western blotting. Cell number was assayedfollowing treatment with exogenous NTs or the Trk phosphorylationinhibitor compound K-252a. Secretion of NTs following exogenousadministration of NTs was determined using immunoassays.Results: LC cells and ONH astrocytes express Trk receptors that arephosphorylated in response to exogenous NTs. Autocrine/paracrinesignaling was also evident by Trk phosphorylation in the absence ofexogenous NT treatment. ONH astrocyte cell number increased followingexogenous treatment with each NT. LC cell number increased followingexogenous NGF or NT-3 treatment only. Treatment with the Trkphosphorylation inhibitor K-252a decreased both LC and ONH astrocytecell number. Exogenous NT treatment increased the secretion of NGF by LCcells and ONH astrocytes. BDNF secretion by LC cells and ONH astrocyteswas decreased by exogenous NT treatment.Conclusions: LC cells and ONH astrocytes express functional Trkreceptors that can be activated in response to exogenous NTs. Theactivation of Trk receptors expressed by LC cells and ONH astrocytes inthe absence of exogenous NT treatment suggests autocrine/paracrine NTsignaling may occur within the ONH. Neurotrophin signaling in LC cellsand ONH astrocytes may regulate cell number and/or NT secretion withinthe LC region of the ONH.

[学科分类] 生物化学/生物物理