Saturday, March 14, 2009

Salubrinal

 Hiroki Yokota participated in this study.

Salubrinal Reduces Expression and Activity of MMP13 in Chondrocytes.

"Stress to the endoplasmic reticulum (ER) and inflammatory cytokines induce expression and activity of matrix metalloproteinase 13 (MMP13). Since a synthetic agent, salubrinal, is known to alleviate ER stress and attenuate nuclear factor kappa B (NFκB) signaling, we addressed a question whether upregulation of MMP13 by ER stress and cytokines is suppressed by administration of salubrinal.
Using C28/I2 human chondrocytes, we applied ER stress with tunicamycin and inflammatory distress with tumor necrosis factor α (TNFα) and interleukin 1β (IL1β). RNA interference with siRNA specific to NFκB p65 (RelA) was employed to examine a potential involvement of NFκB signaling in salubrinal's action in regulation of MMP13. We also employed primary human chondrocytes and evaluated MMP13 activity.
Tunicamycin activated p38 MAPK, while inflammatory cytokines activated p38 MAPK and NFκB. In both cases, salubrinal significantly reduced expression and activity of MMP13. Silencing NFκB reduced inflammatory cytokine-driven upregulation of MMP13 activity.
Salubrinal downregulates expression and activity MMP13 through p38 and NFκB signaling."

Now MMP13 is actually essentially for endochondral ossification.

"elevation of the level of phosphorylated eIF2a leads to expression of activating transcription factor 4 (ATF4)"<-salubrinal inhibits EIF2a dephosphorylation.

"In response to 10 ng/ml IL1b and 1 mg/ml tunicamycin, the mRNA levels of MMP1, MMP2{up}, and MMP14{up} were not altered, but the level of MMP3{up} mRNA was elevated"

"salubrinal decreased the level of p-IKK that was known to downregulate the NFkB inhibitor, IkB"

This study does present a clear linkage between Salubrinal and height but doesn't rule out increase applications.

"Tunicamycin is an inhibitor of N-linked glycosylation and the formation of N-glycosidic protein-carbohydrate linkages"

"Tunicamycin increased the level of eIF2a phosphorylation (p-eIF2a) at 1 h, followed by an elevation in the level of ATF4 at 3 h"

"Co-incubation with tunicamycin and salubrinal presented an increase in p-eIF2a and ATF4"

"Tunicamycin induced phosphorylation of p38 MAPK (p-p38 MAPK) at 1 and 2 h, while administration of 10 mM salubrinal suppressed the tunicamycin-induced increase in p-p38 MAPK"  Tunicaymin did not activate NFkB.

The following article is by the LSJL lab:

Effects of salubrinal on development of osteoclasts and osteoblasts from bone marrow-derived cells.

"Osteoporosis is a skeletal disease leading to an increased risk of bone fracture. Using a mouse osteoporosis model induced by administration of a receptor activator of nuclear factor kappa-B ligand (RANKL), salubrinal was recently reported as a potential therapeutic agent. To evaluate the role of salubrinal in cellular fates as well as migratory and adhesive functions of osteoclast/osteoblast precursors, we examined the development of primary bone marrow-derived cells in the presence and absence of salubrinal{so we can see any potential effects of BM-MSCs on salubrinal for LSJL}.
Using the RANKL-injected and control mice, bone marrow-derived cells were harvested. Osteoclastogenesis was induced by macrophage-colony stimulating factor and RANKL, while osteoblastogenesis was driven by dexamethasone, ascorbic acid, and beta-glycerophosphate.
Salubrinal suppressed the numbers of colony forming-unit (CFU)-granulocyte/macrophages and CFU-macrophages, as well as formation of mature osteoclasts in a dosage-dependent manner. Salubrinal also suppressed migration and adhesion of pre-osteoclasts and increased the number of CFU-osteoblasts. Salubrinal was more effective in exerting its effects in the cells isolated from the RANKL-injected mice than the control. Consistent with cellular fates and functions, salubrinal reduced the expression of nuclear factor of activated T cells c1 (NFATc1) as well as tartrate-resistant acid phosphatase.
Salubrinal exhibits significant inhibition of osteoclastogenesis as well as stimulation of osteoblastogenesis in bone marrow-derived cells, and its efficacy is enhanced in the cells harvested from the osteoporotic bone samples."

We need of Salubrinal's effects on MSC's pre-differentiation to see if it can have an impact on LSJL.

"Salubrinal is reported to attenuate molecular signaling mediated by nuclear factor kappa B (NFκB)"

"C57BL/6 female mice (7 weeks of age) were used"

"mRNA and  protein expression of NFATc1 is downregulated by salubrinal. NFATc1 is a member of the
NFAT transcription factor family and a master transcription factor for osteoclast development. NFATc1-deficient embryonic stem cells are unable to differentiate into osteoclasts"

"MafB (V-maf musculoaponeurotic fibrosarcoma oncogene homolog B), IRF8 (interferon regulatory factor
8), and Bcl6 (V cell lymphoma) have been mentioned as inhibitors of NFATc1"<-Salubrinal may act through these inhibitors and if it does in turn the effects of these inhibitors could have importance for LSJL.

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