Biomedical subjects
Julia Polak
Publications and source records attributed to Julia Polak.
Endothelial nitric oxide synthase in the control of osteoblastic mineralizing activity and bone integrity.
It has been shown previously that osteoblast differentiation and maintenance of bone mass are impaired in endothelial nitric oxide synthase gene knockout mice. The present study shows by analysis of messenger RNA expression that the transcription factor Cbfa-1/Runx-2 and the bone matrix protein osteocalcin, which are fundamental to osteoblast differentiation, are significantly reduced in neonatal calvarial osteoblasts from these gene knockout mice. Expression of these genes could be restored to wild-type levels by exogenous supply of the photoactivatable nitric oxide donor potassium nitrosylpentachlorouthenate, but this was dependent on the timing of its activation and recovery in gene expression was only evident during the latter stages of osteoblast differentiation associated with its mineralizing activity. Calvarial, femoral/pelvic, spinal, and total bone mineral density, together with bone microhardness and expression of osteocalcin in whole femurs, were all reduced significantly in gene knockout mice at 8 weeks of age, but not at 12 weeks, where all of these indices of bone integrity were comparable to wild type. In accordance with these temporal effects, reduced bone mineral density, bone microhardness, and osteocalcin expression could be restored to normal, wild-type values after 21 days in vivo administration of the nitric oxide donor glyceryl trinitrate to 4-week-old endothelial nitric oxide synthase knockout mice, but there was no significant effect in older animals. Taken together, these results further demonstrate the importance of endothelial nitric oxide synthase in the regulation of osteoblast metabolism. In particular, they show that nitric oxide is involved in co-ordinating specific phases of osteoblast differentiation and bone formation: this could be relevant to its therapeutic actions on bone turnover.
Expression of lymphotoxin-beta (LT-beta) in chronic inflammatory conditions.
Functional studies in gene-knockout and transgenic mice systems have shown that lymphotoxin-alpha and lymphotoxin-beta (LT-alpha and LT-beta) are of fundamental importance in peripheral lymphoid organ development, but it remains unclear what role these cytokines have to play in the adult immune response and in the pathogenesis of disease. In this study, a polyclonal anti-serum to human LT-beta was used to investigate the distribution of LT-beta by immunohistochemistry in normal and diseased tissues. In the gut, lymph nodes, spleen, and tonsil, there was some LT-beta present on a variety of lymphoid cell types. In contrast, strong staining for LT-beta was observed on plasma cells and a subpopulation of CD4+ T cells in tissues affected by chronic inflammatory disease or infection, for example in inflammatory bowel disease, and in lymph nodes obtained from patients with sarcoidosis and tuberculosis. In tuberculous and sarcoid lymph nodes, LT-beta expression also occurred on some but not all epithelioid histiocytes within granulomas and on multi-nucleated giant cells. These findings support a role for LT-beta in human disease and suggest that it might represent a therapeutic target in a variety of common infective or inflammatory disorders.