AUTHOR=Persson Emma , Souza Pedro P. C. , Floriano-Marcelino Thais , Conaway Howard Herschel , Henning Petra , Lerner Ulf H. 

TITLE=Activation of Shc1 Allows Oncostatin M to Induce RANKL and Osteoclast Formation More Effectively Than Leukemia Inhibitory Factor

JOURNAL=Frontiers in Immunology

VOLUME=Volume 10 - 2019

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.01164

DOI=10.3389/fimmu.2019.01164

ISSN=1664-3224

ABSTRACT=Background and purpose: The gp130 family of cytokines signals through receptors dimerizing with the gp130 subunit. Downstream signalling typically activates STAT3 but also SHP2/Ras/MAPK pathways. Oncostatin M (OSM) is a unique cytokine in this family since the receptor (OSMR) activates a non-redundant signalling pathway by recruitment of the adapter ShcA. We have studied the functional relevance of ShcA for OSM-induced bone resorption. Experimental approach: Osteoblasts were stimulated with OSM and STAT3 and ShcA activations were studied using real-time PCR and Western blots. The role of STAT3 and ShcA for OSM-induced RANKL expression and osteoclast formation was studied by silencing their mRNA expressions. Effects of OSM were compared to those of the closely related cytokine leukemia inhibitory factor (LIF). 
Key results: OSM, but not LIF, induced the mRNA and protein expression of ShcA and activated phosphorylation of ShcA in the osteoblasts. Silencing of ShcA decreased OSM-induced activation of STAT3 and RANKL expression. Silencing of STAT3 had no effect on activation of ShcA, but prevented the OSM-mediated increase of RANKL expression. Silencing of either ShcA or STAT3 in osteoblasts decreased formation of osteoclasts in OSM-stimulated co-cultures of osteoblasts and macrophages. In agreement with these observations, OSM was a more potent and robust stimulator than LIF of RANKL formation and bone resorption in mouse calvariae and osteoclast formation in bone marrow cultures. 
Conclusions and implications: Activation of the ShcA-dependent STAT3 signalling is crucial for OSM-induced osteoclast formation. Inhibition of ShcA is a potential mechanism to specifically inhibit OSM-induced bone resorption.