ABSTRACT
OBJECTIVE: The role of postmenopause on the pathogenesis of cartilage degeneration has been an open question. We assessed cartilage degeneration in estrogen receptor (ER)alpha null mice and examined the role of glucocorticoid receptor-interacting protein 1 (GRIP1) in the ERalpha-dependent transcription of a type II collagen gene (col2a1) with special reference to a crosstalk with the transforming growth factor (TGF)-beta signaling pathway. METHODS: The vertebral cartilaginous endplate from female ERalpha null mice was subjected to histological analyses. Col2a1 expression of primary chondrocytes (PCs) obtained from ERalpha null mice after 17beta-estradiol (E(2)) and TGF-beta1 stimulation was examined by reverse transcription polymerase chain reaction (RT-PCR). Estrogen response element (ERE) or col2a1 promoter-enhancer luciferase reporter system was used to investigate the crosstalk among ERalpha, GRIP1, and MKK6. Col2a1 expression and glycosaminoglycan (GAG) content were measured in ATDC5 cells treated with GRIP1 small interfering RNA (siRNA). RESULTS: ERalpha deficiency clearly accelerated impairment of the vertebral cartilaginous endplate. E(2) and TGF-beta1 stimulation increased col2a1 expression in PC from wild-type mice, but not that from ERalpha null mice. The same stimulation increased the col2a1 promoter-enhancer reporter activity, and the elevated activity was decreased by dominant-negative ERalpha and p38 mitogen-activated protein kinase (MAPK) inhibitor. GRIP1 increased the E(2)-dependent ERE activation in the presence of ERalpha and constitutive-active MKK6. GRIP1 siRNA repressed col2a1 expression and GAG production in ATDC5 cells. CONCLUSIONS: Crosstalks between ERalpha/GRIP1 and TGF-beta/MKK6/p38 MAPK pathway have protective roles on cartilage metabolism via regulating the extracellular matrices expression. The finding may lead to the development of a novel therapeutic approach for cartilage degeneration.
Subject(s)
Carrier Proteins/genetics , Cartilage/metabolism , Chondrocytes/metabolism , Estrogen Receptor alpha/genetics , MAP Kinase Kinase 6/genetics , Nerve Tissue Proteins/genetics , Age Factors , Animals , Estrogen Receptor alpha/metabolism , Female , Gene Expression Regulation , Intervertebral Disc/metabolism , MAP Kinase Kinase 6/metabolism , Mice , Models, Animal , Pregnancy , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Calcitropic hormones, such as calcitonin and vitamin D, are one of the most common drugs used in the treatment of osteoporosis. Recently, three enzymes involved in vitamin D metabolism (25-hydroxylase, 24-hydroxylase, 1alpha-hydroxylase) were cloned and enabled us to analyze the vitamin D metabolism at a molecular level. We summarize the mechanism which CT activates vitamin D.
ABSTRACT
Vitamin D and PTH are major hormones that regulate calcium metabolism. Also, the serum level of phosphorus is known to change according to the level of calcium and to regulate the vitamin D and PTH. Recently, cloning of 1alpha- hydroxylase cDNA which is the key enzyme in vitamin D metabolism, enabled us to examine the effects of phosphorus in vitamin D metabolism at a molecular level. Furthermore, the direct effect of phosphorus in PTH synthesis is being elucidated in recent reports. In this paper, we summarized the regulation of vitamin D and PTH by phosphorus.
ABSTRACT
The plasma profile and parallel plasma flow in the scrape-off layer (SOL) were systematically measured using reciprocating Mach probes installed at the outer midplane and near the divertor magnetic null (x point) in the JT-60U tokamak with a single null divertor. For the ion vertical drift due to the toroidal magnetic field gradient (ion nablaB drift) directed towards the divertor, SOL plasma flow along the magnetic field lines away from the divertor ("flow reversal") was discovered at the midplane far from the divertor. A quantitative evaluation of the ion "Pfirsch-Schluter flow," wherein the parallel flow is naturally produced in a toroidal plasma, was consistent with the measurement.
