The inhibitors of cyclin-dependent kinases and GSK-3β enhance osteoclastogenesis

Abstract

Osteoclasts are multinucleated cells with bone resorption activity that is crucial for bone remodeling. RANK‐RANKL (receptor activator of nuclear factor κB ligand) signaling has been shown as a main signal pathway for osteoclast differentiation. However, the molecular mechanism and the factors regulating osteoclastogenesis remain to be fully understood. In this study, we performed a chemical genetic screen, and identified a Cdks/GSK-3β (cyclin-dependent kinases/glycogen synthase kinase 3β) inhibitor, kenpaullone, and two Cdks inhibitors, olomoucine and roscovitine, all of which significantly enhance osteoclastogenesis of RAW264.7 cells by upregulating NFATc1 (nuclear factor of activated T cells, cytoplasmic 1) levels. We also determined that the all three compounds increase the number of osteoclast differentiated from murine bone marrow cells. Furthermore, the three inhibitors, especially kenpaullone, promoted maturation of cathepsin K, suggesting that the resorption activity of the resultant osteoclasts is also activated. Our findings indicate that inhibition of GSK-3β and/or Cdks enhance osteoclastogenesis by modulating the RANK–RANKL signaling pathway.

Identification of a factor controlling lysosomal homeostasis using a novel lysosomal trafficking probe

“…Although these two compounds are structurally different, both potentially inhibit CDK1, CDK2, CDK4, and CDK5 26,27 . Indeed, treatment with these compounds induces cell cycle arrest at any cycle stage 33,34 . We hypothesised that organelle growth continued even after cell cycle arrest caused by the inhibitor and resulted in increased numbers of lysosomes.…”

Construction of an artificial system for ambrein biosynthesis and investigation of some biological activities of ambrein

“…8). The effect of 50 μM 1 was similar to that of 5 μM kenpaullone 22 , which is a strong activator of osteoclastic differentiation. This result suggested that 1 may be a promising drug candidate for osteopetrosis, caused by defective osteoclast function.…”

Design, Synthesis and in Vitro Tumor Cytotoxicity Evaluation of 3,5‐Diamino‐N‐substituted Benzamide Derivatives as Novel GSK‐3β Small Molecule Inhibitors

“…As a signal transduction pathway of PI3 K/Akt, GSK‐3 β is used as the substrate to interact directly with Akt, resulting in the inactivation of GSK‐3 β phosphorylation . The decrease of GSK‐3 β ‐LKB1‐Axis protein complex increases β ‐catenin accumulation, the acceleration of cell transcription, the up‐regulation of c‐Myc, c‐Jun, Cyclin D1 expression and the promotion of tumor cell proliferation . Besides, GSK‐3 β activates the Wnt signaling pathway through phosphorylated substrates, and the abnormal activation of Wnt/ β ‐catenin pathway is closely related to the development of colorectal cancer, gastric cancer and other tumors .…”

“…[21,22] The decrease of GSK-3β-LKB1-Axis protein complex increases β-catenin accumulation, the acceleration of cell transcription, the up-regulation of c-Myc, c-Jun, Cyclin D1 expression and the promotion of tumor cell proliferation. [23] Besides, GSK-3β activates the Wnt signaling pathway through phosphorylated substrates, and the abnormal activation of Wnt/β-catenin pathway is closely related to the development of colorectal cancer, gastric cancer and other tumors. [24,25] GSK-3β promotes the activation of NF-κB by acting on TNF-α (tumor necrosis factor), [26] promotes the proliferation and differentiation of tumor cells and enhances the ability of invasion and metastasis of tumor cells.…”