Working Paper Article Version 1 This version is not peer-reviewed

Dual Effects of Vericiguat on Osteoclast Differentiation and Bone Resorption via a Balance between VASP and NF-κB Pathways

Version 1 : Received: 8 September 2021 / Approved: 8 September 2021 / Online: 8 September 2021 (13:02:05 CEST)

How to cite: Sun, K.; Kong, F.; Lin, F.; Li, F.; Sun, J.; Ren, C.; Zheng, B.; Shi, J. Dual Effects of Vericiguat on Osteoclast Differentiation and Bone Resorption via a Balance between VASP and NF-κB Pathways. Preprints 2021, 2021090151 Sun, K.; Kong, F.; Lin, F.; Li, F.; Sun, J.; Ren, C.; Zheng, B.; Shi, J. Dual Effects of Vericiguat on Osteoclast Differentiation and Bone Resorption via a Balance between VASP and NF-κB Pathways. Preprints 2021, 2021090151

Abstract

The nature of bone homeostasis is the coordination between the osteoblasts (OBs) and osteoclasts (OCs). However, abnormal activation of osteoclasts (OCs) could compromise the bone homeostasis. Thus, it is imperatively urgent to explore effective medical interventions for patients. NO/guanylate cyclase (GC)/cGMP signaling cascade has been widely reported in regulating bone metabolism, and GC plays a significantly critical role. Vericiguat, a novel oral soluble guanylate cyclase (sGC) stimulator, has been firstly reported in 2020 to treat patients with heart failure. However, the effect of Vericiguat on the function of OCs has not been explored. In this present study, we found that the concentration range of Vericiguat between 0-8uM was none- cytotoxic to BMMs. Vericiguat could enhance differentiation of OCs at concentration of 500nM, whereas it inhibited differentiation at 8 uM in terms of the number and size of OCs. In addition, Veirciguat also showed dural effect on RANKL‐induced OC fusion and bone resorption in a concentration‐dependent manner. Further, molecular assay suggested that the dually regulatory effect of Vericiguat on OCs was mediated by the bidirectional activation of IκB-α/NF-κB signaling pathway. Taken together, our present study demonstrated the dual effects of Vericiguat on the formation of functional OCs in a concentration-dependent manner. The regulatory effect of Vericiguat on OCs was mediated by the bidirectional activation of IκB-α/ NF-κB signaling pathway, and a potential balance between IκB-α/ NF-κB signaling pathway and sGC/cGMP/VASP may exist.

Keywords

Vericiguat; osteoclast (OCs), MAPK, NF-κB; RANKL; AKT, molecular mechanism

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