Regulation of ITAM adaptor molecules and their receptors by inhibition of calcineurin-NFAT signalling during late stage osteoclast differentiation
Abstract
Osteoclasts are specialised bone resorptive cells responsible for both physiological and pathological bone loss. Osteoclast differentiation and activity is dependent upon receptor activator NF-kappa-B ligand (RANKL) interacting with its receptor RANK to induce the transcription factor, nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1). The immunoreceptor tyrosine-based activation motif (ITAM)-dependent pathway has been identified as a co-stimulatory pathway in osteoclasts. Osteoclast-associated receptor (OSCAR) and triggering receptor expressed in myeloid cells (TREM2) are essential receptors that pair with adaptor molecules Fc receptor common gamma chain (FcRγ) and DNAX-activating protein 12kDa (DAP12) respectively to induce calcium signalling. Treatment with calcineurin-NFAT inhibitors, Tacrolimus (FK506) and the 11R-VIVIT (VIVIT) peptide, reduces NFATc1 expression consistent with a reduction in osteoclast differentiation and activity. This study aimed to investigate the effects of inhibiting calcineurin-NFAT signalling on the expression of ITAM factors and late stage osteoclast genes including cathepsin K (CathK), Beta 3 integrin (β3) and Annexin VIII (AnnVIII). Human peripheral blood mononuclear cells (PBMCs) were differentiated with RANKL and macrophage-colony stimulating factor (M-CSF) over 10days in the presence or absence of FK506 or VIVIT. Osteoclast formation (as assessed by tartrate resistant acid phosphatase (TRAP)) and activity (a…
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In RANKL-activated HSCs, polyubiquitination of NIK is inhibited and TRAF6 activates a cascade of kinases including ERK, p38, JNK, PI3K, Akt, and IkB kinases.
“In RANKL-activated HSCs, polyubiquitination of NIK is inhibited [18], and TRAF6 activates a cascade of kinases, including extracellular regulated kinase (ERK), p38 mitogen-activated protein kinase (p38), c-jun N-terminal kinase (JNK), phosphatidylinositol-3 kinase (PI3K), and Akt and IkB kinases [20,21].”
From Osteoclasts and Microgravity (2020) · cites this paper as [21]
The calcineurin pathway is a key costimulatory pathway of NFATc1 and an important signaling component of a number of immune cell receptors.
“This activates cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and the calcineurin pathway [21,24,25,27], a key costimulatory pathway of NFATc1 [21,23] and an important signaling component of a number of immune cell receptors [28] (Figure 4 and Figure 5).”
From Osteoclasts and Microgravity (2020) · cites this paper as [21]
Cites
The role of NFAT in osteoclast formation
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Ishida, N., Hayashi, K., Hoshijima, M., Ogawa, T., Koga, S., Miyatake, Y., Kumegawa, M., Kimura, T., & Takeya, T. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205063200 · Cited by 377 · see citing works
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Smith, J. K. (2020) · Life · doi:10.3390/life10090207 · Cited by 52 · see citing works
- Authors
- Zawawi, M. S. F., Dharmapatni, A. A. S. S. K., Cantley, M. D., McHugh, K. P., Haynes, D. R., & Crotti, T. N.
- Affiliations
- Universiti Sains Malaysia (MY)
- The University of Adelaide (AU)
- University of Florida (US)
- Corresponding author
- Crotti, T.N.
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 427
- Issue
- 2
- Pages
- 404-409
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2055372799
- Cited by
- 29
- References
- 2
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 2 · 2021: 1 · 2020: 3 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 3 · 2015: 7 · 2014: 4 · 2013: 1 · 2012: 1
- FWCI
- 1.67
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Keywords
- osteoclastogenesis, tacrolimus, ITAM, RANKL, RANK, NFATc1, osteoclast-associated receptor, TREM2, FcRγ, DAP12, cathepsin K, CD61, bone resorption, bone loss, immunosuppressive therapy
- MeSH terms
- Cell Differentiation, Cells, Cultured, Humans, Membrane Glycoproteins, Oligopeptides, Osteoclasts, Receptors, Cell Surface, Receptors, Immunologic, Gene Expression, Tacrolimus, Receptors, IgG, NFATC Transcription Factors, Immunoreceptor Tyrosine-Based Activation Motif, Calcineurin Inhibitors
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