Combined low-dose LiCl and LY294002 for the treatment of osteoporosis in ovariectomized rats

Jianhai Bai,Yan Dieo,Guicai Sun,Yier Xu

doi:10.1186/s13018-019-1210-1

Abstract

BackgroundTo provide a low-toxicity and high-efficacy clinical treatment for osteoporosis via a novel combination of LiCl and LY294002.MethodsThe protein levels of p-AKT, AKT, p-GSK3β, GSK3β, β-catenin, p-β-catenin, and NFATC1 were measured in osteoblasts and osteoclasts by Western blot. ALP activity and TRACP activity were measured using the corresponding kit. The levels of BALP, PINP, CTX, and TRACP-5b were determined in accordance with the requirements of the ELISA kits. Microstructural analysis was performed on the left distal femur using microcomputed tomography.ResultsTreatment with the combination of LiCl and LY294002 led to a markedly increased osteoblast activity but significantly decreased osteoclast differentiation and bone absorption capacity compared with the treatment with LiCl or LY294002 alone (P < 0.01). In serum, the low-dose combination of LiCl and LY294002 significantly enhanced BALP levels (P < 0.01) and significantly decreased PINP, TRACP-5b, and CTX levels (P < 0.01) compared with the application of either drug alone.ConclusionsThis study indicates that drug combinations directed at multiple targets could be used for osteoporosis treatment by promoting osteoblast proliferation and inhibiting differentiation with high efficiency.

Highlights

To provide a low-toxicity and high-efficacy clinical treatment for osteoporosis via a novel combination of lithium chloride (LiCl) and LY294002
The control and model groups were administered in the same volume of phosphatebuffered saline (PBS), whereas the other three groups were injected with LiCl (10 mM), LY294002 (using 0.1– 0.3% dimethylsulfoxide (DMSO) as a vehicle control and dissolved at 0.1%, 10 μM), or LiCl (5 mM) + LY294002 (5 μM) [14, 15]
Effects of LiCl and LY294002 alone and in combination on the AKT/glycogen synthase kinase 3-β (GSK3β)/β-catenin/NFATC1 signaling pathway in osteoblasts and osteoclasts Figure 1a shows the alterations in AKT/GSK3β/β-catenin/NFATC1 signaling in osteoblasts after treatment with LiCl or LY294002 alone or treatment with the lowdose combination of LiCl and LY294002

Summary

Introduction

To provide a low-toxicity and high-efficacy clinical treatment for osteoporosis via a novel combination of LiCl and LY294002. Bone remodeling includes formation and resorption processes mediated by osteoblasts and osteoclasts, respectively [1]. The balance between bone formation and absorption is disrupted with age, and both the mechanical strength and mass of bone decrease because of the loss of bone cell function through bone tissue microstructural deterioration, decreased trace elements and salt levels, and increased osteoblast apoptosis, all of which increase bone porosity and are considered symptoms of osteoporosis [2, 3]. The main treatment for osteoporosis is stimulating bone formation or inhibiting bone resorption [4]. The Wnt and AKT signal transduction pathways can promote osteoblast proliferation and inhibit osteoclast differentiation [7, 8].

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