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L-tetrahydropalmatine suppresses osteoclastogenesis in vivo and in vitro via blocking RANK-TRAF6 interactions and inhibiting NF-?B and MAPK pathways.

ABSTRACT: Bone homeostasis is delicately orchestrated by osteoblasts and osteoclasts. Various pathological bone loss situations result from the overactivated osteoclastogenesis. Receptor activator of nuclear factor ?B ligand (RANKL)-activated NF-?B and MAPK pathways is vital for osteoclastogenesis. Here, we for the first time explored the effects of l-tetrahydropalmatine (l-THP), an active alkaloid derived from corydalis, on the formation and function of osteoclasts in vitro and in vivo. In RAW264.7 cells and bone marrow monocytes cells (BMMCs), l-THP inhibited osteoclastic differentiation at the early stage, down-regulated transcription level of osteoclastogenesis-related genes and impaired osteoclasts functions. Mechanically, Western blot showed that l-THP inhibited the phosphorylation of P50, P65, I?B, ERK, JNK and P38, and the electrophoretic mobility shift assay (EMSA) revealed that DNA binding activity of NF-?B was suppressed, ultimately inhibiting the expression of nuclear factor of activated T cells (NFATc1). Besides, Co-immunoprecipitation indicated that l-THP blocked the interactions of RANK and TNF receptor associated factor 6 (TRAF6) at an upstream site. In vivo, l-THP significantly inhibited ovariectomy-induced bone loss and osteoclastogenesis in mice. Collectively, our study demonstrated that l-THP suppressed osteoclastogenesis by blocking RANK-TRAF6 interactions and inhibiting NF-?B and MAPK pathways. l-THP is a promising agent for treating osteoclastogenesis-related diseases such as post-menopausal osteoporosis.

SUBMITTER: Zhi X

PROVIDER: S-EPMC6933417 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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l-tetrahydropalmatine suppresses osteoclastogenesis in vivo and in vitro via blocking RANK-TRAF6 interactions and inhibiting NF-κB and MAPK pathways.

Zhi Xin X Wang Lipeng L Chen Huiwen H Fang Chao C Cui Jin J Hu Yan Y Cao Liehu L Weng Weizong W Zhou Qirong Q Qin Longjuan L Song Hongyuan H Wang Yajun Y Wang Yao Y Jiang Hao H Li Xiaoqun X Wang Sicheng S Chen Xiao X Su Jiacan J

Journal of cellular and molecular medicine 20191114 1

Bone homeostasis is delicately orchestrated by osteoblasts and osteoclasts. Various pathological bone loss situations result from the overactivated osteoclastogenesis. Receptor activator of nuclear factor κB ligand (RANKL)-activated NF-κB and MAPK pathways is vital for osteoclastogenesis. Here, we for the first time explored the effects of l-tetrahydropalmatine (l-THP), an active alkaloid derived from corydalis, on the formation and function of osteoclasts in vitro and in vivo. In RAW264.7 cells ...[more]

PMID: 31725199

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Project description:Background: Aseptic loosening of prosthesis (ALP) is one of the most common long-term complications of knee and hip arthroplasty. Wear particle-induced osteoclastogenesis and subsequent periprosthetic osteolysis account for the morbidity of ALP. Here, we investigate the potential of cimifugin (CIM), a natural extract from Cimicifuga racemosa and Saposhnikovia divaricata, as a bone-protective drug in the treatment of ALP. Method: First, we performed cell viability and osteoclast formation assays to assess the effect of noncytotoxic CIM on osteoclast differentiation in vitro. Bone slice resorption and F-actin ring immunofluorescence assays were adopted to assess the effects of CIM on bone-resorption function. Then, quantitative real-time polymerase chain reaction (qRT-PCR) analysis was performed to further assess the repressive effects of CIM on osteoclastogenesis at the gene expression level. To elucidate the mechanisms underlying the above findings, Western blot and luciferase reporter gene assays were used to assess the regulatory effects of CIM on the NF-κB and MAPK signaling pathways. Moreover, a Ti particle-induced murine calvarial osteolysis model and subsequent histomorphometric analysis via micro-CT and immunohistochemical staining were used to elucidate the effect of CIM on periprosthetic osteolysis in vivo. Result: CIM dose-dependently inhibited both bone marrow-derived macrophage (BMM)- and RAW264.7 cell-derived osteoclastogenesis and bone resorption pit formation in vitro, which was further supported by the reduced expression of F-actin and osteoclast-specific genes. According to the Western blot analysis, inhibition of IκBα phosphorylation in the NF-κB signaling pathway, not the phosphorylation of MAPKs, was responsible for the suppressive effect of CIM on osteoclastogenesis. Animal experiments demonstrated that CIM alleviated Ti particle-induced bone erosion and osteoclast accumulation in murine calvaria. Conclusion: The current study suggested for the first time that CIM can inhibit RANKL-induced osetoclastogenesis by suppressing the NF-κB signaling pathway in vitro and prevent periprosthetic osteolysis in vivo. These findings suggest the potential of CIM as a therapeutic in ALP.

Dataset Information

L-tetrahydropalmatine suppresses osteoclastogenesis in vivo and in vitro via blocking RANK-TRAF6 interactions and inhibiting NF-?B and MAPK pathways.

Publications

l-tetrahydropalmatine suppresses osteoclastogenesis in vivo and in vitro via blocking RANK-TRAF6 interactions and inhibiting NF-κB and MAPK pathways.

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