Skip to main content
Top

Open Access 25-03-2024 | Multiple Myeloma | ORIGINAL ARTICLE

Halofuginone Inhibits Osteoclastogenesis and Enhances Osteoblastogenesis by Regulating Th17/Treg Cell Balance in Multiple Myeloma Mice with Bone Lesions

Authors: Xiaofei Wu, Qiong Sun, Xiang Li, Lin Jiang, Li Chen

Published in: Indian Journal of Hematology and Blood Transfusion

Login to get access

Abstract

Evidences shows that T helper 17 (Th17) and regulatory T (Treg) cells imbalance plays a critical role in bone lesions of MM patients. Therefore, regulating the Th17/Treg imbalance may be beneficial for bone lesions in MM. Ten MM mice complicated with bone lesions were established and divided into the halofuginone (HF) group and the PBS group. After treatment, tibia and fibula from both groups were scanned by micro-CT. Osteoclasts and osteoblasts were validated by histochemical staining and ELISA. Th17 and Treg cells were tested by flow cytometry. The correlations between Th17/Treg cell ratio and osteoclasts, osteoblasts and bone remodeling were analyzed using the Spearman relative analysis. After treatment, mice in the HF group had an increase in trabecular bone volume fraction and thickened cortex, but a decrease in trabecular separation compared to mice in the PBS group.Tartrate-resistant acid phosphase (TRAP) + osteoclasts and its biomarker TRACP5b in serum were reduced, while alkaline phosphatase (ALP) + osteoblasts and its biomarker N-terminal propeptide of type 1precollagen (P1NP) in serum were accreted in the HF group. Th17/Treg cell ratio in halofuginone-treated mice was 0.85 ± 0.05, and was significantly lower than that in PBS-treated mice, which was 1.51 ± 0.03. In addition, it showed that the Th17/Treg cell ratio was significantly and positively associated with osteoclasts, but was significantly and negatively associated with osteoblasts and bone remodeling. Halofuginone plays a critical role in the amelioration bone lesions in MM, as it can inhibit osteoclastogenesis and enhance osteoblastogenesis by regulating the Th17/Treg cell balance.
Appendix
Available only for authorised users
Literature
1.
go back to reference Guo N, Song Y, Zi F, Zheng J, Cheng J (2023) Abnormal expression pattern of lncRNA H19 participates in multiple myeloma bone disease by unbalancing osteogenesis and osteolysis. Int Immunopharmacol 119:110058CrossRefPubMed Guo N, Song Y, Zi F, Zheng J, Cheng J (2023) Abnormal expression pattern of lncRNA H19 participates in multiple myeloma bone disease by unbalancing osteogenesis and osteolysis. Int Immunopharmacol 119:110058CrossRefPubMed
2.
go back to reference Huang B, Liu H, Chan S, Liu J, Gu J et al (2023) RUNX2 promotes the suppression of osteoblast function and enhancement of osteoclast activity by multiple myeloma cells. Med Oncol 40(4):115CrossRefPubMedPubMedCentral Huang B, Liu H, Chan S, Liu J, Gu J et al (2023) RUNX2 promotes the suppression of osteoblast function and enhancement of osteoclast activity by multiple myeloma cells. Med Oncol 40(4):115CrossRefPubMedPubMedCentral
4.
go back to reference O’Donnell EK, Raje NS (2017) Myeloma bone disease: pathogenesis and treatment. Clin Adv Hematol Oncol 15(4):285–295PubMed O’Donnell EK, Raje NS (2017) Myeloma bone disease: pathogenesis and treatment. Clin Adv Hematol Oncol 15(4):285–295PubMed
5.
go back to reference Vallet S, Mukherjee S, Vaghela N, Hideshima T, Fulciniti M et al (2010) Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease. Proc Natl Acad Sci U S A 107(11):5124–5129CrossRefPubMedPubMedCentral Vallet S, Mukherjee S, Vaghela N, Hideshima T, Fulciniti M et al (2010) Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease. Proc Natl Acad Sci U S A 107(11):5124–5129CrossRefPubMedPubMedCentral
6.
go back to reference Tsubaki M, Seki S, Takeda T, Chihara A, Arai Y et al (2020) The HGF/Met/NF-κB pathway regulates RANKL expression in osteoblasts and bone marrow stromal cells. Int J Mol Sci 21(21):7905CrossRefPubMedPubMedCentral Tsubaki M, Seki S, Takeda T, Chihara A, Arai Y et al (2020) The HGF/Met/NF-κB pathway regulates RANKL expression in osteoblasts and bone marrow stromal cells. Int J Mol Sci 21(21):7905CrossRefPubMedPubMedCentral
7.
go back to reference Simic MK, Mohanty ST, Xiao Y, Cheng TL, Taylor VE et al (2023) Multi-Targeting DKK1 and LRP6 Prevents Bone Loss and Improves Fracture Resistance in Multiple Myeloma. J Bone Miner Res 38(6):814–828CrossRefPubMed Simic MK, Mohanty ST, Xiao Y, Cheng TL, Taylor VE et al (2023) Multi-Targeting DKK1 and LRP6 Prevents Bone Loss and Improves Fracture Resistance in Multiple Myeloma. J Bone Miner Res 38(6):814–828CrossRefPubMed
9.
go back to reference Feng P, Yan R, Dai X, Xie X, Wen H, Yang S (2015) The alteration and clinical significance of Th1/Th2/Th17/Treg cells in patients with multiple myeloma. Inflammation 38(2):705–709CrossRefPubMed Feng P, Yan R, Dai X, Xie X, Wen H, Yang S (2015) The alteration and clinical significance of Th1/Th2/Th17/Treg cells in patients with multiple myeloma. Inflammation 38(2):705–709CrossRefPubMed
10.
go back to reference Ben Hmid A, Selmi O, Rekik R, Lamari H, Zamali I (2020) RORC overexpression as a sign of Th17 lymphocytes accumulation in multiple myeloma bone marrow. Cytokine 134:155210CrossRefPubMed Ben Hmid A, Selmi O, Rekik R, Lamari H, Zamali I (2020) RORC overexpression as a sign of Th17 lymphocytes accumulation in multiple myeloma bone marrow. Cytokine 134:155210CrossRefPubMed
11.
go back to reference Dong M, Zhang J, Chen Q, He D, Yan H et al (2022) High serum IL-17A is associated with bone destruction in newly diagnosed multiple myeloma patients. Front Oncol 12:936670CrossRefPubMedPubMedCentral Dong M, Zhang J, Chen Q, He D, Yan H et al (2022) High serum IL-17A is associated with bone destruction in newly diagnosed multiple myeloma patients. Front Oncol 12:936670CrossRefPubMedPubMedCentral
12.
go back to reference Ma T, Zhang Y, Zhou X, Xie P, Li J (2020) A unique role of T helper 17 cells in different treatment stages of multiple myeloma. Clin Lymphoma Myeloma Leuk 20(3):190–197CrossRefPubMed Ma T, Zhang Y, Zhou X, Xie P, Li J (2020) A unique role of T helper 17 cells in different treatment stages of multiple myeloma. Clin Lymphoma Myeloma Leuk 20(3):190–197CrossRefPubMed
13.
go back to reference Gao R, Zhang W, Jiang Y, Zhai J, Yu J et al (2023) Eldecalcitol effectively prevents alveolar bone loss by partially improving Th17/Treg cell balance in diabetes-associated periodontitis. Front Bioeng Biotechnol 11:1070117CrossRefPubMedPubMedCentral Gao R, Zhang W, Jiang Y, Zhai J, Yu J et al (2023) Eldecalcitol effectively prevents alveolar bone loss by partially improving Th17/Treg cell balance in diabetes-associated periodontitis. Front Bioeng Biotechnol 11:1070117CrossRefPubMedPubMedCentral
14.
go back to reference Runyan CE, Liu Z, Schnaper HW (2012) Phosphatidylinositol 3-kinase and Rab5 GTPase inversely regulate the Smad anchor for receptor activation (SARA) protein independently of transforming growth factor-β1. J Biol Chem 287(43):35815–35824CrossRefPubMedPubMedCentral Runyan CE, Liu Z, Schnaper HW (2012) Phosphatidylinositol 3-kinase and Rab5 GTPase inversely regulate the Smad anchor for receptor activation (SARA) protein independently of transforming growth factor-β1. J Biol Chem 287(43):35815–35824CrossRefPubMedPubMedCentral
15.
go back to reference Ren X, Zhang M, Zhang W, Xie J, Luo H et al (2022) Yunnan Baiyao ameliorates rheumatoid arthritis in rats by shifting the Th17/Treg cell balance and preventing osteoclast differentiation. Evid Based Complement Alternat Med 2022:3764444CrossRefPubMedPubMedCentral Ren X, Zhang M, Zhang W, Xie J, Luo H et al (2022) Yunnan Baiyao ameliorates rheumatoid arthritis in rats by shifting the Th17/Treg cell balance and preventing osteoclast differentiation. Evid Based Complement Alternat Med 2022:3764444CrossRefPubMedPubMedCentral
16.
go back to reference Wang J, Wang B, Lv X, Wang Y (2020) Halofuginone functions as a therapeutic drug for chronic periodontitis in a mouse model. Int J Immunopathol Pharmacol 34:2058738420974893CrossRefPubMedPubMedCentral Wang J, Wang B, Lv X, Wang Y (2020) Halofuginone functions as a therapeutic drug for chronic periodontitis in a mouse model. Int J Immunopathol Pharmacol 34:2058738420974893CrossRefPubMedPubMedCentral
17.
go back to reference Park MK, Park JS, Park EM, Lim MA, Kim SM et al (2014) Halofuginone ameliorates autoimmune arthritis in mice by regulating the balance between Th17 and Treg cells and inhibiting osteoclastogenesis. Arthritis Rheumatol 66(5):1195–1207CrossRefPubMed Park MK, Park JS, Park EM, Lim MA, Kim SM et al (2014) Halofuginone ameliorates autoimmune arthritis in mice by regulating the balance between Th17 and Treg cells and inhibiting osteoclastogenesis. Arthritis Rheumatol 66(5):1195–1207CrossRefPubMed
18.
go back to reference Leiba M, Jakubikova J, Klippel S, Mitsiades CS, Hideshima T et al (2012) Halofuginone inhibits multiple myeloma growth in vitro and in vivo and enhances cytotoxicity of conventional and novel agents. Br J Haematol 157(6):718–731CrossRefPubMedPubMedCentral Leiba M, Jakubikova J, Klippel S, Mitsiades CS, Hideshima T et al (2012) Halofuginone inhibits multiple myeloma growth in vitro and in vivo and enhances cytotoxicity of conventional and novel agents. Br J Haematol 157(6):718–731CrossRefPubMedPubMedCentral
19.
go back to reference Sumitani Y, Hamba H, Nakamura K, Sadr A, Nikaido T, Tagami J (2018) Micro-CT assessment of comparative radiopacity of adhesive/composite materials in a cylindrical cavity. Dent Mater J 37(4):634–641CrossRefPubMed Sumitani Y, Hamba H, Nakamura K, Sadr A, Nikaido T, Tagami J (2018) Micro-CT assessment of comparative radiopacity of adhesive/composite materials in a cylindrical cavity. Dent Mater J 37(4):634–641CrossRefPubMed
20.
go back to reference Zhang Q, Hu S, He Y, Song Z, Shen Y et al (2022) Monotropein protects against inflammatory bone loss and suppresses osteoclast formation and bone resorption by inhibiting NFATc1 via NF-κB and Akt/GSK-3β pathway. Nutrients 14(19):3978CrossRefPubMedPubMedCentral Zhang Q, Hu S, He Y, Song Z, Shen Y et al (2022) Monotropein protects against inflammatory bone loss and suppresses osteoclast formation and bone resorption by inhibiting NFATc1 via NF-κB and Akt/GSK-3β pathway. Nutrients 14(19):3978CrossRefPubMedPubMedCentral
22.
go back to reference Monnerat S, Refardt J, Potasso L, Meier C, Christ-Crain M (2023) An increase in plasma sodium levels is associated with an increase in osteoblast function in chronic SIAD. J Clin Endocrinol Metab 108(10):e1027–e1033CrossRefPubMedPubMedCentral Monnerat S, Refardt J, Potasso L, Meier C, Christ-Crain M (2023) An increase in plasma sodium levels is associated with an increase in osteoblast function in chronic SIAD. J Clin Endocrinol Metab 108(10):e1027–e1033CrossRefPubMedPubMedCentral
23.
go back to reference Chen JR, Lazarenko OP, Blackburn ML, Chen JF, Randolph CE et al (2022) Nox4 expression in osteo-progenitors controls bone development in mice during early life. Commun Biol 5(1):583CrossRefPubMedPubMedCentral Chen JR, Lazarenko OP, Blackburn ML, Chen JF, Randolph CE et al (2022) Nox4 expression in osteo-progenitors controls bone development in mice during early life. Commun Biol 5(1):583CrossRefPubMedPubMedCentral
24.
go back to reference Carlson TJ, Pellerin A, Djuretic IM, Trivigno C, Koralov SB et al (2014) Halofuginone-induced amino acid starvation regulates Stat3-dependent Th17 effector function and reduces established autoimmune inflammation. J Immunol 192(5):2167–2176CrossRefPubMed Carlson TJ, Pellerin A, Djuretic IM, Trivigno C, Koralov SB et al (2014) Halofuginone-induced amino acid starvation regulates Stat3-dependent Th17 effector function and reduces established autoimmune inflammation. J Immunol 192(5):2167–2176CrossRefPubMed
25.
go back to reference Hou X, Zhou J, Yang R, Liu S, Bi M et al (2017) Effect of halofuginone on the pathogenesis of autoimmune thyroid disease in different mice models. Endocr Metab Immune Disord Drug Targets 17(2):141–148CrossRefPubMed Hou X, Zhou J, Yang R, Liu S, Bi M et al (2017) Effect of halofuginone on the pathogenesis of autoimmune thyroid disease in different mice models. Endocr Metab Immune Disord Drug Targets 17(2):141–148CrossRefPubMed
26.
go back to reference Zhan W, Kang Y, Chen N, Mao C, Kang Y, Shang J (2017) Halofuginone ameliorates inflammation in severe acute hepatitis B virus (HBV)-infected SD rats through AMPK activation. Drug Des Devel Ther 11:2947–2955CrossRefPubMedPubMedCentral Zhan W, Kang Y, Chen N, Mao C, Kang Y, Shang J (2017) Halofuginone ameliorates inflammation in severe acute hepatitis B virus (HBV)-infected SD rats through AMPK activation. Drug Des Devel Ther 11:2947–2955CrossRefPubMedPubMedCentral
27.
go back to reference Bettelli E, Carrier Y, Gao W, Korn T, Strom TB et al (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441(7090):235–238CrossRefPubMed Bettelli E, Carrier Y, Gao W, Korn T, Strom TB et al (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441(7090):235–238CrossRefPubMed
28.
go back to reference Rossi M, Altomare E, Botta C, Gallo Cantafio ME, Sarvide S et al (2021) miR-21 antagonism abrogates Th17 tumor promoting functions in multiple myeloma. Leukemia 35(3):823–834CrossRefPubMed Rossi M, Altomare E, Botta C, Gallo Cantafio ME, Sarvide S et al (2021) miR-21 antagonism abrogates Th17 tumor promoting functions in multiple myeloma. Leukemia 35(3):823–834CrossRefPubMed
29.
go back to reference Ke D, Fu X, Xue Y, Wu H, Zhang Y et al (2018) IL-17A regulates the autophagic activity of osteoclast precursors through RANKL-JNK1 signaling during osteoclastogenesis in vitro. Biochem Biophys Res Commun 497(3):890–896CrossRefPubMed Ke D, Fu X, Xue Y, Wu H, Zhang Y et al (2018) IL-17A regulates the autophagic activity of osteoclast precursors through RANKL-JNK1 signaling during osteoclastogenesis in vitro. Biochem Biophys Res Commun 497(3):890–896CrossRefPubMed
30.
go back to reference Wang Z, Wei Y, Lei L, Zhong J, Shen Y et al (2021) RANKL expression of primary osteoblasts is enhanced by an IL-17-mediated JAK2/STAT3 pathway through autophagy suppression. Connect Tissue Res 62(4):411–426CrossRefPubMed Wang Z, Wei Y, Lei L, Zhong J, Shen Y et al (2021) RANKL expression of primary osteoblasts is enhanced by an IL-17-mediated JAK2/STAT3 pathway through autophagy suppression. Connect Tissue Res 62(4):411–426CrossRefPubMed
31.
go back to reference Taylor A, Verhagen J, Blaser K, Akdis M, Akdis CA (2006) Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: the role of T regulatory cells. Immunology 117(4):433–442CrossRefPubMedPubMedCentral Taylor A, Verhagen J, Blaser K, Akdis M, Akdis CA (2006) Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: the role of T regulatory cells. Immunology 117(4):433–442CrossRefPubMedPubMedCentral
Metadata
Title
Halofuginone Inhibits Osteoclastogenesis and Enhances Osteoblastogenesis by Regulating Th17/Treg Cell Balance in Multiple Myeloma Mice with Bone Lesions
Authors
Xiaofei Wu
Qiong Sun
Xiang Li
Lin Jiang
Li Chen
Publication date
25-03-2024
Publisher
Springer India
Published in
Indian Journal of Hematology and Blood Transfusion
Print ISSN: 0971-4502
Electronic ISSN: 0974-0449
DOI
https://doi.org/10.1007/s12288-024-01756-4
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine