Salubrinal decreases osteoclastgenesis

This study doesn’t relate directly to height growth but it is by the scientists whose research was the foundation for LSJL.

In vitro and in silico analysis of an inhibitory mechanism of osteoclastogenesis by Salubrinal and Guanabenz

“Synthetic agents such as salubrinal and guanabenz, which attenuate stress to the endoplasmic reticulum, are reported to inhibit development of osteoclasts. However, the mechanism of their inhibitory action on osteoclasts is largely unknown. Using genome-wide expression profiles, we predicted key transcription factors that downregulated nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a master transcription factor for osteoclastogenesis. Principal component analysis (PCA) predicted a list of transcription factors that were potentially responsible for reversing receptor activator of nuclear factor kappa-B ligand (RANKL)-driven stimulation of osteoclastogenesis. A partial silencing of NFATc1 allowed a selection of transcription factors that were likely to be located upstream of NFATc1. We validated the predicted transcription factors by focusing on two AP-1 transcription factors (c-Fos and JunB) using RAW264.7 pre-osteoclasts as well as primary bone marrow cells. As predicted, their mRNA and protein levels were elevated by RANKL, and the elevation was suppressed by salubrinal and guanabenz. A partial silencing of c-Fos or JunB by RNA interference decreased salubrinal- and guanabenz-driven reduction of NFATc1 as well as tartrate-resistant acid phosphatase (TRAP) mRNA. Collectively, a systems-biology approach allows the prediction of a RANKL-salubrinal/guanabenz-NFATc1 regulatory axis, and in vitro assays validate an involvement of AP-1 transcription factors in suppression of osteoclastogenesis.”

“Salubrinal and guanabenz are potent chemical agents for the inhibition of protein phosphatase 1 (PP1) that specifically de-phosphorylate eIF2α. Through upregulating the phosphorylated level of eIF2α and reducing translational efficiency of most proteins except for a limited set of proteins, such ATF4, these agents attenuate stress to the endoplasmic reticulum. Gene regulation by salubrinal and guanabenz, however, not only takes place at the level of translation but also at the level of transcription. In osteoclasts, it has been shown that administration of salubrinal and guanabenz suppresses receptor activator of nuclear factor kappa-B ligand (RANKL)-driven activation of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) ”

“A partial silencing of c-Fos and JunB decreased the mRNA and protein levels of NFATc1. Furthermore, there was a feedback loop in which a decrease in c-Fos by salubrinal reduced NFATc1 expression, and the reduction in NFATc1 further attenuated the level of c-Fos protein. AP-1 proteins are known to play a critical role in osteoclast differentiation. It is reported that mice lacking c-Fos are osteopetrotic due to abnormal development of osteoclasts”

Unfortunately, no real LSJL insights in this study.

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