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Glaucocalyxin A suppresses osteoclastogenesis induced by RANKL and osteoporosis induced by ovariectomy by inhibiting the NF-κB and Akt pathways.
J Ethnopharmacol. 2021 Aug 10; 276:114176.JE

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE

Glaucocalyxin A (GLA), the most abundant active component of the aboveground sections of Rabdosia japonica (Burm. f.) Hara var. glaucocalyx (Maxim.) Hara, possesses various pharmacological activities, such as antioxidant, antithrombosis, anticoagulation, antibacterial, antitumor, anti-inflammatory activities. According to previous studies, inflammation is closely associated with osteoclast differentiation and activity. Although GLA has demonstrated effective anti-inflammatory properties, its effects on osteoclast differentiation remain unclear.

AIM OF THE STUDY

To examine the possible inhibitory effects of GLA and its molecular mechanisms in osteogenesis induced by RANKL as well as ovariectomy (OVX)-induced osteoporosis (OP) in mice.

MATERIALS AND METHODS

Tartrate-resistant acid phosphatase (TRAP) staining, F-actin staining, and a bone resorption pit assay were applied for identifying the effects of GLA on the differentiation of osteoclasts and the function of bone resorption. The mRNA expression of the genes related to osteoclast differentiation was measured by quantitative PCR. Protein expression of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), c-fos and phosphorylation of inhibitor of nuclear factor kappa B (IκBα), protein kinase B (AKT), c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 in RANKL-induced osteoclasts was determined using western blotting. The effect of GLA on OP was studied using a mouse model of OVX.

RESULTS

At nontoxic concentrations ≤0.5 μM in vitro, GLA suppressed the formation of osteoclasts induced by RANKL with the decreased number and area size of TRAP-positive multinuclear osteoclasts, and the resorption of bone function by reducing F-actin ring number and bone resorption pit areas. It also reduced the expression of the genes specific for osteoclasts, which included genes encoding NFATc1, cathepsin K, c-fos, TRAP, vacuolar-type ATPase d2, and dendritic cell-specific transmembrane protein. Moreover, GLA repressed NF-κB and Akt pathway activation induced by RANKL. Micro-CT analysis of femur samples indicated decreased bone loss and greater trabecular bone density after GLA treatment, which showed that GLA played a protective role by inhibiting bone loss in OVX-induced OP mice in vivo.

CONCLUSIONS

Our study is the first to show that GLA has significant therapeutic potential in OP, which is the disease of osteoclast increase caused by estrogen deficiency.

Authors+Show Affiliations

Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Artificial Joints Engineering and Technology Research Center of Jiangxi Province, Nanchang, Jiangxi province, 330006, China. Electronic address: zhumeisongv@163.com.Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Artificial Joints Engineering and Technology Research Center of Jiangxi Province, Nanchang, Jiangxi province, 330006, China. Electronic address: 454776398@qq.com.Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Artificial Joints Engineering and Technology Research Center of Jiangxi Province, Nanchang, Jiangxi province, 330006, China. Electronic address: 18370655730@163.com.Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Artificial Joints Engineering and Technology Research Center of Jiangxi Province, Nanchang, Jiangxi province, 330006, China. Electronic address: 510688327@qq.com.Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Artificial Joints Engineering and Technology Research Center of Jiangxi Province, Nanchang, Jiangxi province, 330006, China. Electronic address: xuqiangyisheng@126.com.Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Artificial Joints Engineering and Technology Research Center of Jiangxi Province, Nanchang, Jiangxi province, 330006, China. Electronic address: quankun201066@sina.cn.Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Artificial Joints Engineering and Technology Research Center of Jiangxi Province, Nanchang, Jiangxi province, 330006, China. Electronic address: shliuxuqiang@163.com.Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Artificial Joints Engineering and Technology Research Center of Jiangxi Province, Nanchang, Jiangxi province, 330006, China. Electronic address: daiminyisheng@163.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33933570

Citation

Zhu, Meisong, et al. "Glaucocalyxin a Suppresses Osteoclastogenesis Induced By RANKL and Osteoporosis Induced By Ovariectomy By Inhibiting the NF-κB and Akt Pathways." Journal of Ethnopharmacology, vol. 276, 2021, p. 114176.
Zhu M, Shan J, Xu H, et al. Glaucocalyxin A suppresses osteoclastogenesis induced by RANKL and osteoporosis induced by ovariectomy by inhibiting the NF-κB and Akt pathways. J Ethnopharmacol. 2021;276:114176.
Zhu, M., Shan, J., Xu, H., Xia, G., Xu, Q., Quan, K., Liu, X., & Dai, M. (2021). Glaucocalyxin A suppresses osteoclastogenesis induced by RANKL and osteoporosis induced by ovariectomy by inhibiting the NF-κB and Akt pathways. Journal of Ethnopharmacology, 276, 114176. https://doi.org/10.1016/j.jep.2021.114176
Zhu M, et al. Glaucocalyxin a Suppresses Osteoclastogenesis Induced By RANKL and Osteoporosis Induced By Ovariectomy By Inhibiting the NF-κB and Akt Pathways. J Ethnopharmacol. 2021 Aug 10;276:114176. PubMed PMID: 33933570.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Glaucocalyxin A suppresses osteoclastogenesis induced by RANKL and osteoporosis induced by ovariectomy by inhibiting the NF-κB and Akt pathways. AU - Zhu,Meisong, AU - Shan,Jing, AU - Xu,Huaen, AU - Xia,Guoming, AU - Xu,Qiang, AU - Quan,Kun, AU - Liu,Xuqiang, AU - Dai,Min, Y1 - 2021/04/30/ PY - 2021/03/09/received PY - 2021/04/16/revised PY - 2021/04/26/accepted PY - 2021/5/3/pubmed PY - 2021/5/3/medline PY - 2021/5/2/entrez KW - Akt KW - Glaucocalyxin A KW - NF-κB KW - Osteoclastogenesis KW - Osteoporosis KW - Ovariectomized mice SP - 114176 EP - 114176 JF - Journal of ethnopharmacology JO - J Ethnopharmacol VL - 276 N2 - ETHNOPHARMACOLOGICAL RELEVANCE: Glaucocalyxin A (GLA), the most abundant active component of the aboveground sections of Rabdosia japonica (Burm. f.) Hara var. glaucocalyx (Maxim.) Hara, possesses various pharmacological activities, such as antioxidant, antithrombosis, anticoagulation, antibacterial, antitumor, anti-inflammatory activities. According to previous studies, inflammation is closely associated with osteoclast differentiation and activity. Although GLA has demonstrated effective anti-inflammatory properties, its effects on osteoclast differentiation remain unclear. AIM OF THE STUDY: To examine the possible inhibitory effects of GLA and its molecular mechanisms in osteogenesis induced by RANKL as well as ovariectomy (OVX)-induced osteoporosis (OP) in mice. MATERIALS AND METHODS: Tartrate-resistant acid phosphatase (TRAP) staining, F-actin staining, and a bone resorption pit assay were applied for identifying the effects of GLA on the differentiation of osteoclasts and the function of bone resorption. The mRNA expression of the genes related to osteoclast differentiation was measured by quantitative PCR. Protein expression of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), c-fos and phosphorylation of inhibitor of nuclear factor kappa B (IκBα), protein kinase B (AKT), c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 in RANKL-induced osteoclasts was determined using western blotting. The effect of GLA on OP was studied using a mouse model of OVX. RESULTS: At nontoxic concentrations ≤0.5 μM in vitro, GLA suppressed the formation of osteoclasts induced by RANKL with the decreased number and area size of TRAP-positive multinuclear osteoclasts, and the resorption of bone function by reducing F-actin ring number and bone resorption pit areas. It also reduced the expression of the genes specific for osteoclasts, which included genes encoding NFATc1, cathepsin K, c-fos, TRAP, vacuolar-type ATPase d2, and dendritic cell-specific transmembrane protein. Moreover, GLA repressed NF-κB and Akt pathway activation induced by RANKL. Micro-CT analysis of femur samples indicated decreased bone loss and greater trabecular bone density after GLA treatment, which showed that GLA played a protective role by inhibiting bone loss in OVX-induced OP mice in vivo. CONCLUSIONS: Our study is the first to show that GLA has significant therapeutic potential in OP, which is the disease of osteoclast increase caused by estrogen deficiency. SN - 1872-7573 UR - https://www.unboundmedicine.com/medline/citation/33933570/Glaucocalyxin_A_suppresses_osteoclastogenesis_induced_by_RANKL_and_osteoporosis_induced_by_ovariectomy_by_inhibiting_the_NF_κB_and_Akt_pathways_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-8741(21)00403-7 DB - PRIME DP - Unbound Medicine ER -