Plumbagin is a NF-κB-inducing kinase inhibitor with dual anabolic and antiresorptive effects that prevents menopausal-related osteoporosis in mice

Gengyang Shen,Xin Liu,Wei Lei,Rong Duan,Zhenqiang Yao

doi:10.1016/j.jbc.2022.101767

Gengyang Shen, Xin Liu + Show 3 more

Open Access

https://doi.org/10.1016/j.jbc.2022.101767

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Abstract

Osteoporosis is caused by enhanced bone resorption and relatively reduced bone formation. There is an unmet need to develop new agents with both antiresorptive and anabolic effects to treat osteoporosis, although drugs with either effect alone are available. A small molecular compound, plumbagin, was reported to inhibit receptor activator of nuclear factor kappa-B ligand–induced osteoclast (OC) differentiation by inhibiting IκBα phosphorylation–mediated canonical NF-κB activation. However, the key transcriptional factor RelA/p65 in canonical NF-κB pathway functions to promote OC precursor survival but not terminal OC differentiation. Here, we found that plumbagin inhibited the activity of NF-κB inducing kinase, the key molecule that controls noncanonical NF-κB signaling, in an ATP/ADP-based kinase assay. Consistent with this, plumbagin inhibited processing of NF-κB2 p100 to p52 in the progenitor cells of both OCs and osteoblasts (OBs). Interestingly, plumbagin not only inhibited OC but also stimulated OB differentiation in vitro. Importantly, plumbagin prevented trabecular bone loss in ovariectomized mice. This was associated with decreased OC surfaces on trabecular surface and increased parameters of OBs, including OB surface on trabecular surface, bone formation rate, and level of serum osteocalcin, compared to vehicle-treated mice. In summary, we conclude that plumbagin is a NF-κB-inducing kinase inhibitor with dual anabolic and antiresorptive effects on bone and could represent a new class of agent for the prevention and treatment of osteoporosis.

Highlights

Osteoporosis is a major aging disease characterized by decreased bone mass and strength, resulting in increased fracture risk
Osteoporosis is caused by an imbalanced bone remodeling, a process involving in enhanced bone resorption and relatively reduced bone formation mediated by osteoclast (OC) and osteoblast (OB), respectively [1]
NF-κB family of transcriptional factors plays a central role in OC differentiation by sequentially activating c-Fos followed by NFATc1 [19, 20], the two other transcriptional factors critical for OC differentiation; [2] NF-κB-inducing kinase (NIK), the key kinase that activates noncanonical NF-κB signaling by processing NF-κB2 p100 into p52, controls Receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis and the development of peripheral lymph nodes and B and T lymphocytes, and NIK deficiency results in the complete resistance of the mice to antigen-induced arthritis [21]; and [3] NIK controls canonical NF-κB activation [22]

Summary

Introduction

Osteoporosis is a major aging disease characterized by decreased bone mass and strength, resulting in increased fracture risk. We report here that plumbagin inhibits OC formation and stimulates OB differentiation by inhibiting NIK activity and the subsequent NF-κB2 p100 processing and efficiently prevents osteoporosis in ovariectomized mice. We found that 0.1 and 0.3 μM of plumbagin significantly increased alkaline phosphatase (ALP)+ OB differentiation but higher dose (1 μM) inhibited it from BM stromal cells (Fig. 2B left panel).

Results

Conclusion