Skip to main content
SpringerLink
Log in

IL-3 inhibits rat osteoclast differentiation induced by TNF-α and other pro-osteoclastogenic cytokines

Journal of Biosciences volume 46, Article number: 63 (2021) Cite this article

Abstract

IL-3, a haematopoiesis regulatory factor, has previously been shown to inhibit both mouse and human osteoclast differentiation and bone resorption. Here, the role of rat IL-3 on rat osteoclast differentiation was evaluated to address whether the inhibitory action of IL-3 on osteoclastogenesis is conserved in various species. It was observed that IL-3 inhibited rat osteoclast differentiation induced by both TNF-α and receptor activator of NF-κB ligand (RANKL). TNF-α is known to induce bone loss in postmenopausal osteoporotic women and it also synergise with many pro-osteoclastogenic cytokines to cause huge pathological bone loss. Importantly, it was found that rat IL-3 inhibits the synergistic action of TNF-α with RANKL and IL-1β, TGF-β1 and TGF-β3. IL-3 downregulates the TNF-α-induced nuclear translocation of NF-κB-p65 and c-fos without affecting c-jun. Interestingly, we observed that IL-3 also inhibits osteoclast differentiation in vivo in rats induced by TNF-α. All these results suggest that inhibitory action of IL-3 on osteoclastogenesis is conserved in various species including mice, rats and humans. Thus, our results clearly indicate that IL-3 has therapeutic potential to treat pathological bone loss in important skeletal diseases.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Abbreviations

RANKL:

Receptor activator of NF-κB ligand

MSCs:

Mesenchymal stem cells

M-CSF:

Macrophage colony-stimulating factor

α-MEM:

Minimal essential medium-alpha modification

TRAP:

Tartrate-resistant acid phosphatase

MNCs:

Multinuclear cells

CTR:

Calcitonin receptor

References

  • Abe T, Chow JW, Lean JM and Chambers TJ 1993 Estrogen does not restore bone lost after ovariectomy in the rat. J. Bone Mineral Res. 8 831–838

    Article  CAS  Google Scholar 

  • Abu-Amer Y 2009 Inflammation, cancer, and bone loss. Curr. Opin. Pharmacol. 9 427–433

    Article  CAS  Google Scholar 

  • Akagawa KS, Takasuka N, Nozaki Y, et al. 1996 Generation of CD1+RelB+ dendritic cells and tartrate-resistant acid phosphatase-positive osteoclast-like multinucleated giant cells from human monocytes. Blood 88 4029–4039

    Article  CAS  Google Scholar 

  • Azuma Y, Kaji K, Katogi R, Takeshita S and Kudo A 2000 Tumor necrosis factor-α induces differentiation of and bone resorption by osteoclasts. J. Biol. Chem. 275 4858–4864

    Article  CAS  Google Scholar 

  • Boyce BF, Xiu Y, Li J, Xing L and Yao Z 2015 NF-κB-mediated regulation of osteoclastogenesis. Endocrinol. Metab. 30 35–44

    Article  CAS  Google Scholar 

  • Braun T and Zwerina J 2011 Positive regulators of osteoclastogenesis and bone resorption in rheumatoid arthritis. Arthritis Res. R. 13 235

    Article  CAS  Google Scholar 

  • Eriksen EF, Hodgson SF, Eastell R, Cedel SL, O’Fallon WM and Riggs BL 1990 Cancellous bone remodeling in type I (postmenopausal) osteoporosis: quantitative assessment of rates of formation, resorption, and bone loss at tissue and cellular levels. J. Bone Mineral Res. 5 311–319

    Article  CAS  Google Scholar 

  • Guise TA 2009 Breaking down bone: New insight into site-specific mechanisms of breast cancer osteolysis mediated by metalloproteinases. Genes Dev. 23 2117–2123

    Article  CAS  Google Scholar 

  • Gupta N, Barhanpurkar AP, Tomar GB, Srivastava RK, Kour S, Pote ST and Wani MR 2010 IL-3 inhibits human osteoclastogenesis and bone resorption through downregulation of c-Fms and diverts the cells to dendritic cell lineage. J. Immunol. 185 2261–2272

    Article  CAS  Google Scholar 

  • Hirayama T 2002 Osteoclast formation and activity in the pathogenesis of osteoporosis in rheumatoid arthritis. Rheumatology 41 1232–1239

    Article  CAS  Google Scholar 

  • Hirose J, Masuda H, Tokuyama N, et al. 2014 Bone resorption is regulated by cell-autonomous negative feedback loop of Stat5-Dusp axis in the osteoclast. J. Exp. Med. 211 153–163

    Article  CAS  Google Scholar 

  • Hong H, Shi Z, Qiao P, et al. 2013 Interleukin-3 plays dual roles in osteoclastogenesis by promoting the development of osteoclast progenitors but inhibiting the osteoclastogenic process. Biochem. Biophy. Res. Commun. 440 545–550

    Article  CAS  Google Scholar 

  • Khapli SM, Mangashetti LS, Yogesha SD and Wani MR 2003 IL-3 Acts Directly on osteoclast precursors and irreversibly inhibits receptor activator of NF-κB ligand-induced osteoclast differentiation by diverting the cells to macrophage lineage. J. Immunol. 171 142–151

    Article  CAS  Google Scholar 

  • Kour S, Garimella MG, Shiroor DA, Mhaske ST, Joshi SR, Singh K and Wani MR 2016 IL-3 decreases cartilage degeneration by downregulating matrix metalloproteinases and reduces joint destruction in osteoarthritic mice. J. Immunol. 196 5024–5035

    Article  CAS  Google Scholar 

  • Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP and Teitelbaum SL 2000 TNF-α induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J. Clin. Invest. 106 1481–1488

    Article  CAS  Google Scholar 

  • Lantz CS, Boesiger J, Song CH, Mach N, Kobayashi T, Mulligan RC and Galli SJ 1998 Role for interleukin-3 in mast-cell and basophil development and in immunity to parasites. Nature 392 90–93

    Article  CAS  Google Scholar 

  • Lee J, Seong S, Kim JH, et al. 2016 STAT5 is a key transcription factor for IL-3-mediated inhibition of RANKL-induced osteoclastogenesis. Sci. Rep. 6 30977

    Article  CAS  Google Scholar 

  • Lee S-K, Kalinowski JF, Jastrzebski SL, Puddington L and Lorenzo JA 2003 Interleukin-7 is a direct inhibitor of in vitro osteoclastogenesis. Endocrinology 144 3524–3531

    Article  CAS  Google Scholar 

  • Martignoni M, Groothuis GMM and De Kanter R 2006 Species differences between mouse, rat, dog, monkey and human cytochrome P450-mediated drug metabolism. Expert Opin. Drug Metab. Toxicol. 2 875–894

    Article  CAS  Google Scholar 

  • Morita Y, Kitaura H, Yoshimatsu M, Fujimura Y, Kohara H, Eguchi T and Yoshida N 2010 IL-18 inhibits TNF-α-induced osteoclastogenesis possibly via a T cell-independent mechanism in synergy with IL-12 in vivo. Calcified Tissue Int. 86 242–248

    Article  CAS  Google Scholar 

  • Nakajima K, Kho DH, Yanagawa T, et al. 2016 Galectin-3 cleavage alters bone remodeling: different outcomes in breast and prostate cancer skeletal metastasis. Cancer Res. 76 1391–1402

    Article  CAS  Google Scholar 

  • Osta B, Benedetti G and Miossec P 2014 Classical and paradoxical effects of TNF-α on bone homeostasis. Front. Immunol. 5 00048

    Google Scholar 

  • Pfeilschifter J, Köditz R, Pfohl M and Schatz H 2002 Changes in proinflammatory cytokine activity after menopause. Endocrine Rev. 23 90–119

    Article  CAS  Google Scholar 

  • Raisz LG 2005 Pathogenesis of osteoporosis: Concepts, conflicts, and prospects. J. Clin. Invest. 115 3318–3325

    Article  CAS  Google Scholar 

  • Ritchlin CT, Haas-Smith SA, Li P, Hicks DG and Schwarz EM 2003 Mechanisms of TNF-α- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J. Clin. Invest. 111 821–831

    Article  CAS  Google Scholar 

  • Roggia C, Gao Y, Cenci S, Weitzmann MN, Toraldo G, Isaia G and Pacifici R 2001 Up-regulation of TNF-producing T cells in the bone marrow: A key mechanism by which estrogen deficiency induces bone loss in vivo. Proc. Nat. Acad. Sci. USA 98 13960–13965

    Article  CAS  Google Scholar 

  • Saeland S, Caux C, Favre C, et al. 1988 Effects of recombinant human interleukin-3 on CD34-enriched normal haematopoietic progenitors and on myeloblastic leukemia cells. Blood 72 1580–1588

    Article  CAS  Google Scholar 

  • Sonoda Y, Yang YC, Wong GG, Clark SC and Ogawa M 1988 Erythroid burst-promoting activity of purified recombinant human GM-CSF and Interleukin-3: Studies with anti-GM-CSF and anti-IL-3 sera and studies in serum free cultures. Blood 72 1381–1386

    Article  CAS  Google Scholar 

  • Turner AS 2001 Animal models of osteoporosis – Necessity and limitations. Eur. Cells Mater. 1 66–81

    Article  CAS  Google Scholar 

  • Wagner EF and Eferl R 2005 Fos/AP-1 proteins in bone and the immune system. Immunol. Rev. 208 126–140

    Article  CAS  Google Scholar 

  • Walsh MC, Takegahara N, Kim H and Choi Y 2018 Updating osteoimmunology: regulation of bone cells by innate and adaptive immunity. Nat. Rev. Rheumatol. 14 146–156

    Article  CAS  Google Scholar 

  • Wang ZQ, Ovitt C, Grigoriadis AE, Möhle-Steinlein U, Rüther U and Wagner EF 1992 Bone and haematopoietic defects in mice lacking c-fos. Nature 360 741–745

    Article  CAS  Google Scholar 

  • Weitzmann MN, Cenci S, Rifas L, Brown C and Pacifici R 2000 Interleukin-7 stimulates osteoclast formation by up-regulating the T-cell production of soluble osteoclastogenic cytokines. Blood 96 1873–1878

    Article  CAS  Google Scholar 

  • Weitzmann MN and Pacifici R 2006 Estrogen deficiency and bone loss: An inflammatory tale. J. Clin. Invest. 116 1186–1194

    Article  CAS  Google Scholar 

  • Yogesha SD, Khapli SM and Wani MR 2005 Interleukin-3 and granulocyte-macrophage colony-stimulating factor inhibits tumor necrosis factor (TNF)- α-induced osteoclast differentiation by down-regulation of expression of TNF receptors 1 and 2. J. Biol. Chem. 280 11759–11769

    Article  CAS  Google Scholar 

  • Yogesha SD, Khapli SM, Srivastava RK, Mangashetti LS, Pote ST, Mishra GC and Wani MR 2009 IL-3 Inhibits TNF-α-induced bone resorption and prevents inflammatory arthritis. J. Immunol. 182 361–370

    Article  CAS  Google Scholar 

  • Yoshimatsu M, Kitaura H, Fujimura Y, Eguchi T, Kohara H, Morita Y and Yoshida N 2009 IL-12 inhibits TNF-α induced osteoclastogenesis via a T cell-independent mechanism in vivo. Bone 45 1010–1016

    Article  CAS  Google Scholar 

  • Zhao B, Grimes SN, Li S, Hu X and Ivashkiv LB 2012 TNF-induced osteoclastogenesis and inflammatory bone resorption are inhibited by transcription factor RBP-J. J. Exp. Med. 209 319–334

    Article  CAS  Google Scholar 

Download references

Acknowledgements

VP is the recipient of a Senior Research Fellowship from the University Grant Commission, New Delhi, India.

Funding

This work was supported by the intramural grant from National Centre for Cell Science, Pune.

Author information

Authors and Affiliations

  1. Bone and Cartilage Research Laboratory, National Centre for Cell Science, S. P. Pune University Campus, Ganeshkhind, Pune, 411 007, India

    Vikrant Piprode, Kanupriya Singh, Anil Kumar, Snehal R. Joshi & Mohan R. Wani

Authors
  1. Vikrant Piprode
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kanupriya Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anil Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Snehal R. Joshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohan R. Wani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohan R. Wani.

Ethics declarations

Animal Rights

The Institutional Animal Ethics Committee approved all animal protocols.

Additional information

Corresponding editor: Dipankar Nandi

Corresponding editor: Dipankar Nandi

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Piprode, V., Singh, K., Kumar, A. et al. IL-3 inhibits rat osteoclast differentiation induced by TNF-α and other pro-osteoclastogenic cytokines. J Biosci 46, 63 (2021). https://doi.org/10.1007/s12038-021-00181-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12038-021-00181-3

Keywords

search

Navigation