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Kalkitoxin Reduces Osteoclast Formation and Resorption and Protects against Inflammatory Bone Loss.
Int J Mol Sci. 2021 Feb 25; 22(5)IJ

Abstract

Osteoclasts, bone-specified multinucleated cells produced by monocyte/macrophage, are involved in numerous bone destructive diseases such as arthritis, osteoporosis, and inflammation-induced bone loss. The osteoclast differentiation mechanism suggests a possible strategy to treat bone diseases. In this regard, we recently examined the in vivo impact of kalkitoxin (KT), a marine product obtained from the marine cyanobacterium Moorena producens (previously Lyngbya majuscula), on the macrophage colony-stimulating factor (M-CSF) and on the receptor activator of nuclear factor κB ligand (RANKL)-stimulated in vitro osteoclastogenesis and inflammation-mediated bone loss. We have now examined the molecular mechanism of KT in greater detail. KT decreased RANKL-induced bone marrow-derived macrophages (BMMs) tartrate-resistant acid phosphatase (TRAP)-multinucleated cells at a late stage. Likewise, KT suppressed RANKL-induced pit area and actin ring formation in BMM cells. Additionally, KT inhibited several RANKL-induced genes such as cathepsin K, matrix metalloproteinase (MMP-9), TRAP, and dendritic cell-specific transmembrane protein (DC-STAMP). In line with these results, RANKL stimulated both genes and protein expression of c-Fos and nuclear factor of activated T cells (NFATc1), and this was also suppressed by KT. Moreover, KT markedly decreased RANKL-induced p-ERK1/2 and p-JNK pathways at different time points. As a result, KT prevented inflammatory bone loss in mice, such as bone mineral density (BMD) and osteoclast differentiation markers. These experiments demonstrated that KT markedly inhibited osteoclast formation and inflammatory bone loss through NFATc1 and mitogen-activated protein kinase (MAPK) signaling pathways. Therefore, KT may have potential as a treatment for destructive bone diseases.

Authors+Show Affiliations

Department of Dental Pharmacology, School of Dentistry, Jeonbuk National University, Jeonju 54896, Korea.Department of Periodontology, School of Dentistry, Jeonbuk National University, Jeon-Ju 561-756, Korea.Department of Dental Pharmacology, School of Dentistry, Jeonbuk National University, Jeonju 54896, Korea.College of Pharmacy, Ajou University, San 5, Woncheon-dong, Youngtong-gu Suwon 443-749, Korea.Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92037, USA.Department of Dental Pharmacology, School of Dentistry, Jeonbuk National University, Jeonju 54896, Korea. Laboratory of Pharmacology, School of Pharmacy, Jeonbuk National University, Jeon-Ju 561-756, Korea.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33669069

Citation

Li, Liang, et al. "Kalkitoxin Reduces Osteoclast Formation and Resorption and Protects Against Inflammatory Bone Loss." International Journal of Molecular Sciences, vol. 22, no. 5, 2021.
Li L, Yang M, Shrestha SK, et al. Kalkitoxin Reduces Osteoclast Formation and Resorption and Protects against Inflammatory Bone Loss. Int J Mol Sci. 2021;22(5).
Li, L., Yang, M., Shrestha, S. K., Kim, H., Gerwick, W. H., & Soh, Y. (2021). Kalkitoxin Reduces Osteoclast Formation and Resorption and Protects against Inflammatory Bone Loss. International Journal of Molecular Sciences, 22(5). https://doi.org/10.3390/ijms22052303
Li L, et al. Kalkitoxin Reduces Osteoclast Formation and Resorption and Protects Against Inflammatory Bone Loss. Int J Mol Sci. 2021 Feb 25;22(5) PubMed PMID: 33669069.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Kalkitoxin Reduces Osteoclast Formation and Resorption and Protects against Inflammatory Bone Loss. AU - Li,Liang, AU - Yang,Ming, AU - Shrestha,Saroj Kumar, AU - Kim,Hyoungsu, AU - Gerwick,William H, AU - Soh,Yunjo, Y1 - 2021/02/25/ PY - 2020/12/25/received PY - 2021/02/19/revised PY - 2021/02/22/accepted PY - 2021/3/6/entrez PY - 2021/3/7/pubmed PY - 2021/5/4/medline KW - bone loss KW - inflammation KW - kalkitoxin KW - marine natural product KW - osteoclast JF - International journal of molecular sciences JO - Int J Mol Sci VL - 22 IS - 5 N2 - Osteoclasts, bone-specified multinucleated cells produced by monocyte/macrophage, are involved in numerous bone destructive diseases such as arthritis, osteoporosis, and inflammation-induced bone loss. The osteoclast differentiation mechanism suggests a possible strategy to treat bone diseases. In this regard, we recently examined the in vivo impact of kalkitoxin (KT), a marine product obtained from the marine cyanobacterium Moorena producens (previously Lyngbya majuscula), on the macrophage colony-stimulating factor (M-CSF) and on the receptor activator of nuclear factor κB ligand (RANKL)-stimulated in vitro osteoclastogenesis and inflammation-mediated bone loss. We have now examined the molecular mechanism of KT in greater detail. KT decreased RANKL-induced bone marrow-derived macrophages (BMMs) tartrate-resistant acid phosphatase (TRAP)-multinucleated cells at a late stage. Likewise, KT suppressed RANKL-induced pit area and actin ring formation in BMM cells. Additionally, KT inhibited several RANKL-induced genes such as cathepsin K, matrix metalloproteinase (MMP-9), TRAP, and dendritic cell-specific transmembrane protein (DC-STAMP). In line with these results, RANKL stimulated both genes and protein expression of c-Fos and nuclear factor of activated T cells (NFATc1), and this was also suppressed by KT. Moreover, KT markedly decreased RANKL-induced p-ERK1/2 and p-JNK pathways at different time points. As a result, KT prevented inflammatory bone loss in mice, such as bone mineral density (BMD) and osteoclast differentiation markers. These experiments demonstrated that KT markedly inhibited osteoclast formation and inflammatory bone loss through NFATc1 and mitogen-activated protein kinase (MAPK) signaling pathways. Therefore, KT may have potential as a treatment for destructive bone diseases. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/33669069/Kalkitoxin_Reduces_Osteoclast_Formation_and_Resorption_and_Protects_against_Inflammatory_Bone_Loss_ L2 - https://www.mdpi.com/resolver?pii=ijms22052303 DB - PRIME DP - Unbound Medicine ER -