Vericiguat Modulates Osteoclast Differentiation and Bone Resorption via a Balance between VASP and NF-κB Pathways

Abstract

Bone homeostasis has been a dynamic equilibrium between osteoclasts (OCs) and osteoblasts (OBs). However, excessive activation of OCs could disturb the bone homeostasis. As a result, effective medical interventions for patients are greatly demanding. NO/guanylate cyclase (GC)/cGMP signaling cascade has been previously reported to regulate bone metabolism, and GC plays a significantly critical role. Vericiguat, as a novel oral soluble guanylate cyclase (sGC) stimulator, has been firstly reported in 2020 to treat patients with heart failure. Nevertheless, the biological effects of Vericiguat on the function of OCs have not yet been explored. In this present study, we found that Vericiguat with the concentration between 0 and 8 μM was noncytotoxic to bone marrow-derived monocyte-macrophage lineage (BMMs). Vericiguat could enhance the differentiation of OCs at concentration of 500 nM, whereas it inhibited OC differentiation at 8 μM. In addition, Vericiguat also showed dual effects on OC fusion and bone resorption in a dose-dependent manner. Furthermore, a molecular assay suggested that the dual regulatory effects of Vericiguat on OCs were mediated by the bidirectional activation of the IκB-α/NF-κB signaling pathway. Taken together, our present study demonstrated the dual effects of Vericiguat on the formation of functional OCs. The regulatory effects of Vericiguat on OCs were achieved by the bidirectional modulation of the IκB-α/NF-κB signaling pathway, and a potential balance between the IκB-α/NF-κB signaling pathway and sGC/cGMP/VASP may exist.

Favorable osteogenic activity of vericiguat doped in β-tricalcium phosphate: In vitro and in vivo studies

“…39 While the primary focus of research on VIT has been on its cardiovascular benefits, some studies have also observed its effects on bone metabolism. 20 Preliminary findings suggest that VIT may have both positive impacts on bone health. 18,20 On one hand, VIT has been shown to promote osteoblast differentiation and activity, which are essential for bone formation.…”

“…20 Preliminary findings suggest that VIT may have both positive impacts on bone health. 18,20 On one hand, VIT has been shown to promote osteoblast differentiation and activity, which are essential for bone formation. 18 By enhancing the levels of cGMP, VIT may stimulate the growth and function of osteoblasts, ultimately contributing to an increase in bone mineral density (BMD).…”

“…18,19 In the context of bone metabolism, the activation of guanylate cyclase activity can have either inhibitory or stimulatory effects on osteoclast differentiation. 20 Studies have shown that mechanical stimulation can induce osteoblast proliferation through activation of guanylate cyclase activity. 21 Vericiguat (VIT), a novel oral soluble guanylate cyclase stimulator, directly generates cyclic guanosine monophosphate and reduce the death incidence from cardio-vascular causes or hospitalization for heart failure patients in 2020.…”

Soluble Guanylyl Cyclase Activators—Promising Therapeutic Option in the Pharmacotherapy of Heart Failure and Pulmonary Hypertension

“…These effects were not seen in adult animals. In these circumstances, the continuation of experimental studies is necessary to solve this problem before starting clinical trials in children [ 50 ].…”

Effects of electrospun membrane surface morphology on cellular behaviours and osteogenesis of bone marrow mesenchymal stem cells

“…Bone repair and regeneration are well-known to be a dynamic and balanced process involving cells such as MSCs, inflammatory cells, osteoblasts, and osteoclasts [22]. BMSCs are commonly used as seed cells in bone tissue engineering because of their ability to self-renew and differentiate multi-directionally [23].…”