Dysregulated energy metabolism impairs chondrocyte function in osteoarthritis.

OBJECTIVES: Metabolic pathways are a series of chemical reactions by which cells take in nutrient substrates for energy and building blocks needed to maintain critical cellular processes. Details of chondrocyte metabolism and how it rewires during the progression of osteoarthritis (OA) are unknown. This research aims to identify what changes in the energy metabolic state occur in OA cartilage. METHODS: Patient matched OA and non-OA cartilage specimens were harvested from total knee replacement patients. Cartilage was first collected for metabolomics, proteomics, and transcriptomics analyses to study global alterations in OA metabolism. We then determined the metabolic routes by tracking [U-13C] isotope with liquid chromatography-mass spectrometry (LC-MS). We further evaluated cellular bioenergetic profiles by measuring oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) and investigated the effects of low-dose and short-term effects of 2-deoxyglucose (2DG) on chondrocytes. RESULTS: OA chondrocytes showed increased basal ECAR and more lactate production compared to non-OA chondrocytes. [U-13C] glucose labelling revealed that less glucose-derived carbon entered the tricarboxylic acid (TCA) cycle. On the other hand, mitochondrial respiratory rates were markedly decreased in the OA chondrocytes compared to non-OA chondrocytes. These changes were accompanied by decreased cellular ATP production, mitochondrial membrane potential and disrupted mitochondrial morphology. We further demonstrated in vitro that short-term inhibition of glycolysis suppressed matrix degeneration gene expression in chondrocytes and bovine cartilage explants cultured under inflammatory conditions. CONCLUSION: This study represents the first comprehensive comparative analysis of metabolism in OA chondrocytes and lays the groundwork for therapeutic targeting of metabolism in OA.

Quorum-sensing linked RNA interference for dynamic metabolic pathway control in Saccharomyces cerevisiae.

Some of the most productive metabolic engineering strategies involve genetic modifications that cause severe metabolic burden on the host cell. Growth-limiting genetic modifications can be more effective if they are 'switched on' after a population growth phase has been completed. To address this problem we have engineered dynamic regulation using a previously developed synthetic quorum sensing circuit in Saccharomyces cerevisiae. The circuit autonomously triggers gene expression at a high population density, and was linked with an RNA interference module to enable target gene silencing. As a demonstration the circuit was used to control flux through the shikimate pathway for the production of para-hydroxybenzoic acid (PHBA). Dynamic RNA repression allowed gene knock-downs which were identified by elementary flux mode analysis as highly productive but with low biomass formation to be implemented after a population growth phase, resulting in the highest published PHBA titer in yeast (1.1mM).

The nonrecurrent inferior laryngeal nerve: review of 33 cases, including two on the left side.

In 6307 cervicotomies for thyroid and parathyroid excision, 33 cases of nonrecurrent inferior laryngeal nerve were identified (0.52%). The anomaly was observed in 31 cases from 4921 dissections on the right side (0.63%) and in two cases from 4673 dissections on the left side (0.04%). Of the 31 patients who were initially seen with this anomaly on the right side, no innominate (brachiocephalic) artery was found; the right common carotid artery was arising directly from the aortic arch. The aberrant subclavian artery could always be felt against the vertebral column behind the esophagus. The two patients with the anomaly on the left side had a right aortic arch associated with situs inversus viscerum. In one case of invasive thyroid carcinoma, the nerve had to be sacrificed. In all of the other patients, postoperative laryngoscopic findings were normal. The nervous anomaly was of vascular anomaly origin in all cases. Predisposing factors for its onset during aortic arch development are discussed. Before surgical treatment, the diagnosis may only be made if vascular anomaly is suspected. Impairment of swallowing is the only clinical symptom to be looked for. The retroesophageal subclavian artery may be detected on chest x-ray films (20%) or by the compression and distortion of the esophagus shown during barium swallow tests (97%). Although rare on the right side and exceptional on the left, an aberrant nonrecurrent pathway for the inferior laryngeal nerve represents a major surgical risk. This is an additional argument in favor of systematic dissection of the inferior laryngeal nerve during thyroid or parathyroid excision.

[The nonrecurrent inferior laryngeal nerve. Apropos of 19 cases including 2 on the left side]. / Le nerf laryngé inférieur non récurrent. A propos de 19 observations dont 2 du côté gauche.

Nineteen cases of non-recurrent inferior laryngeal nerve were identified during 3791 cervicotomies for thyroid or parathyroid excision over the last 7 years, the nervous anomaly being of vascular anomaly origin in all cases. Predisposing factors for its onset during aortic arch development are discussed, together with possible symptomatology and means for preoperative diagnosis. Frequency in the cases reported was 0,54% from 3098 dissections on the right and 0,07% from 2846 dissections on the left. Although rare on the right and exceptional on the left, an aberrant non-recurrent pathway for the inferior laryngeal nerve represents a major, surgical risk during thyroid or parathyroid excision.