Protaetia brevitarsis Extract Attenuates RANKL-Induced Osteoclastogenesis by Inhibiting the JNK/NF-κB/PLCγ2 Signaling Pathway

Protaetia brevitarsis (PB)-derived bioactive substances have been used as food and medicine in many Asian countries because of their antioxidant, antidiabetic, anti-cancer, and hepatoprotective properties. However, the effect of PB extracts (PBE) on osteoclast differentiation is unclear. In this study, we investigated the effect of PBE on RANKL-induced osteoclastogenesis in mouse bone marrow-derived macrophages (BMMs). To investigate the cytotoxicity of PBE, the viability of BMMs was confirmed via MTT assay. Tartrate-resistant acid phosphatase (TRAP) staining and pit assays were performed to confirm the inhibitory effect of PBE on osteoclast differentiation and bone resorption. The expression levels of osteoclast differentiation-related genes and proteins were evaluated using quantitative real-time PCR and Western blotting. PBE attenuated osteoclastogenesis in BMMs in TRAP and pit assays without cytotoxicity. The expression levels of osteoclast marker genes and proteins induced by RANKL were decreased after PBE treatment. PBE suppressed osteoclastogenesis by inhibiting the RANKL-induced activated JNK/NF-κB/PLCγ2 signaling pathway and the expression of NFATc1 and c-Fos. Collectively, these results suggest that PBE could be a potential therapeutic strategy or functional product for osteoclast-related bone disease.

[1]  M. Paik,et al.  Protaetia brevitarsis seulensis larvae ethanol extract inhibits RANKL-stimulated osteoclastogenesis and ameliorates bone loss in ovariectomized mice. , 2023, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[2]  J. E. Aguilar-Toalá,et al.  Beyond Human Nutrition of Edible Insects: Health Benefits and Safety Aspects , 2022, Insects.

[3]  Liangliang Xu,et al.  Dehydromiltirone inhibits osteoclast differentiation in RAW264.7 and bone marrow macrophages by modulating MAPK and NF-κB activity , 2022, Frontiers in Pharmacology.

[4]  Hae-June Lee,et al.  Protective effects of an aqueous extract of Protaetia brevitarsis seulensis larvae against radiation‐induced testicular injury in mice , 2022, Food science & nutrition.

[5]  Xinjia Wang,et al.  Asiatic Acid Attenuates Osteoporotic Bone Loss in Ovariectomized Mice Through Inhibiting NF-kappaB/MAPK/ Protein Kinase B Signaling Pathway , 2022, Frontiers in Pharmacology.

[6]  E. Noh,et al.  Anti-diabetic effects of Protaetia brevitarsis in pancreatic islets and a murine diabetic model. , 2021, European review for medical and pharmacological sciences.

[7]  M. Buzgo,et al.  The Effect of Alendronate on Osteoclastogenesis in Different Combinations of M-CSF and RANKL Growth Factors , 2021, Biomolecules.

[8]  Jong-Suk Kim,et al.  Aqueous extract of Chrysanthemum morifolium Ramat. inhibits RANKL-induced osteoclast differentiation by suppressing the c-fos/NFATc1 pathway. , 2020, Archives of oral biology.

[9]  M. Jeong,et al.  Protaetia brevitarsis seulensis Derived Protein Isolate with Enhanced Osteomodulatory and Antioxidative Property , 2020, Molecules.

[10]  Ju-Young Kim,et al.  Betulinic Acid Inhibits RANKL-Induced Osteoclastogenesis via Attenuating Akt, NF-κB, and PLCγ2-Ca2+ Signaling and Prevents Inflammatory Bone Loss. , 2020, Journal of natural products.

[11]  Daewon Jeong,et al.  Roles of Mitogen-Activated Protein Kinases in Osteoclast Biology , 2018, International journal of molecular sciences.

[12]  Jian Zhang,et al.  Crocin inhibits RANKL‑induced osteoclastogenesis by regulating JNK and NF‑κB signaling pathways. , 2018, Molecular medicine reports.

[13]  Weiguo Zou,et al.  Paracrine and endocrine actions of bone—the functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts , 2018, Bone Research.

[14]  E. Schwarz,et al.  Osteoblast–osteoclast interactions , 2018, Connective tissue research.

[15]  T. Nakashima,et al.  Recent advances in osteoclast biology , 2018, Histochemistry and Cell Biology.

[16]  Soo Young Lee,et al.  Current Understanding of RANK Signaling in Osteoclast Differentiation and Maturation , 2017, Molecules and cells.

[17]  S. Saad,et al.  Fatty acid is a potential agent for bone tissue induction: In vitro and in vivo approach , 2017, Experimental biology and medicine.

[18]  P. Miller,et al.  Western Osteoporosis Alliance Clinical Practice Series: Evaluating the Balance of Benefits and Risks of Long-Term Osteoporosis Therapies. , 2017, The American journal of medicine.

[19]  E. López-Huertas,et al.  Daily Intake of Milk Enriched with n-3 Fatty Acids, Oleic Acid, and Calcium Improves Metabolic and Bone Biomarkers in Postmenopausal Women , 2016, Journal of the American College of Nutrition.

[20]  Wonhwa Lee,et al.  Antithrombotic and antiplatelet activities of small-molecule alkaloids from Scolopendra subspinipes mutilans , 2016, Scientific Reports.

[21]  Hyunsook Kim,et al.  Selective Regulation of MAPK Signaling Mediates RANKL-dependent Osteoclast Differentiation , 2016, International journal of biological sciences.

[22]  P. Calder,et al.  Functional Roles of Fatty Acids and Their Effects on Human Health. , 2015, JPEN. Journal of parenteral and enteral nutrition.

[23]  L. Xing,et al.  NF-κB-Mediated Regulation of Osteoclastogenesis , 2015, Endocrinology and metabolism.

[24]  Zheng-chao Tu,et al.  Bioactive compounds from the insect Aspongopus chinensis. , 2014, Bioorganic & medicinal chemistry letters.

[25]  J. Huh,et al.  Formononetin attenuates osteoclastogenesis via suppressing the RANKL-induced activation of NF-κB, c-Fos, and nuclear factor of activated T-cells cytoplasmic 1 signaling pathway. , 2014, Journal of natural products.

[26]  Eugenia G. Giannopoulou,et al.  RBP-J imposes a requirement for ITAM-mediated costimulation of osteoclastogenesis. , 2014, The Journal of clinical investigation.

[27]  A. Teti,et al.  The Great Beauty of the osteoclast. , 2014, Archives of biochemistry and biophysics.

[28]  A. Fontana,et al.  The biological activities of protein/oleic acid complexes reside in the fatty acid. , 2013, Biochimica et biophysica acta.

[29]  E. Yun,et al.  Fatty Acid Composition and Volatile Constituents of Protaetia brevitarsis Larvae , 2013, Preventive nutrition and food science.

[30]  Ken Goldberg,et al.  Risk factors for osteonecrosis of the jaws: a case-control study from the CONDOR Dental PBRN. , 2013, Texas dental journal.

[31]  S. Ohta,et al.  Dorsamin-A's, glycerolipids carrying a dehydrophenylalanine ester moiety from the seed-eating larvae of the bruchid beetle Bruchidius dorsalis. , 2013, Journal of natural products.

[32]  J. Penninger,et al.  Fos plays an essential role in the upregulation of RANK expression in osteoclast precursors within the bone microenvironment , 2012, Journal of Cell Science.

[33]  Y. Abu-Amer.  NF-κB signaling and bone resorption , 2012, Osteoporosis International.

[34]  N. Sims,et al.  Intercellular Cross-Talk Among Bone Cells: New Factors and Pathways , 2012, Current Osteoporosis Reports.

[35]  Hyunkyoung Lee,et al.  Effects of fermented aloe vera mixed diet on larval growth of Protaetia brevitarsis seulensis (Kolbe) (coleopteran:Cetoniidae) and protective effects of its extract against CCl4‐induced hepatotoxicity in Sprague–Dawley rats , 2012 .

[36]  A. van Huis,et al.  Environmental manipulation for edible insect procurement: a historical perspective , 2012, Journal of Ethnobiology and Ethnomedicine.

[37]  S. Narod.  Hormone replacement therapy and the risk of breast cancer , 2011, Nature Reviews Clinical Oncology.

[38]  J. Putney,et al.  Calcium signaling in osteoclasts. , 2011, Biochimica et biophysica acta.

[39]  A. Trouvin,et al.  Receptor activator of nuclear factor-κB ligand and osteoprotegerin: maintaining the balance to prevent bone loss , 2010, Clinical interventions in aging.

[40]  Jiake Xu,et al.  NF-kappaB modulators in osteolytic bone diseases. , 2009, Cytokine & growth factor reviews.

[41]  P. Choong,et al.  Novel therapeutic strategy for osteosarcoma targeting osteoclast differentiation, bone-resorbing activity, and apoptosis pathway , 2008, Molecular Cancer Therapeutics.

[42]  E. Wagner,et al.  NF-κB p50 and p52 Regulate Receptor Activator of NF-κB Ligand (RANKL) and Tumor Necrosis Factor-induced Osteoclast Precursor Differentiation by Activating c-Fos and NFATc1* , 2007, Journal of Biological Chemistry.

[43]  Y. Yoo,et al.  Isolation of fatty acids with anticancer activity fromProtaetia brevitarsis Larva , 2007, Archives of pharmacal research.

[44]  Hiroshi Takayanagi,et al.  The molecular understanding of osteoclast differentiation. , 2007, Bone.

[45]  R. Faccio,et al.  PLCgamma2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2. , 2006, The Journal of clinical investigation.

[46]  Kozo Nakamura,et al.  Role of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL–RANK signaling system , 2005, Immunological reviews.

[47]  David L. Lacey,et al.  Osteoclast differentiation and activation , 2003, Nature.

[48]  Hiroshi Takayanagi,et al.  Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. , 2002, Developmental cell.

[49]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[50]  Y. Kadono,et al.  Segregation of TRAF6‐mediated signaling pathways clarifies its role in osteoclastogenesis , 2001, The EMBO journal.

[51]  T. Martin,et al.  Therapeutic approaches to bone diseases. , 2000, Science.

[52]  S. Teitelbaum,et al.  Bone resorption by osteoclasts. , 2000, Science.

[53]  T. Miyata,et al.  Commitment and Differentiation of Osteoclast Precursor Cells by the Sequential Expression of C-Fms and Receptor Activator of Nuclear Factor κb (Rank) Receptors , 1999, The Journal of experimental medicine.

[54]  T. Martin,et al.  Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. , 1999, Endocrine reviews.

[55]  J. Manson,et al.  Prospective study of exogenous hormones and risk of pulmonary embolism in women , 1996, The Lancet.

[56]  S. Manolagas,et al.  Role of cytokines in bone resorption. , 1995, Bone.

[57]  Seoung-Hoon Lee,et al.  NFATc1 induces osteoclast fusion via up-regulation of Atp6v0d2 and the dendritic cell-specific transmembrane protein (DC-STAMP). , 2008, Molecular endocrinology.