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Cited by 176Bone Metabolism and DiseasesOsteomyelitis and Bone Disorders ResearchRheumatoid Arthritis Research and Therapies

Action of RANKL and OPG for Osteoclastogenesis

Kobayashi, Yasuhiro, Udagawa, Nobuyuki, Takahashi, Naoyuki·2009·Critical Reviews™ in Eukaryotic Gene Expression
DOI 10.1615/critreveukargeneexpr.v19.i1.30
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Abstract

Osteoclasts develop from hematopoietic cells of the monocyte-macrophage lineage. The coculture system of osteoblasts and hematopoietic cells was devised to examine osteoclastogenesis in vitro. Experiments using the coculture system have established the concept that osteoblasts are crucially involved in osteoclastogenesis. Remarkable progress has been achieved during the last decade in our understanding the molecular mechanism of osteoclast differentiation, largely because of the discovery of receptor activator of NF-kappaB ligand (RANKL), an essential cytokine for osteoclastogenesis. Osteoblasts express RANKL in response to bone-resorbing factors. Osteoblasts also produce osteoprotegerin (OPG), a decoy receptor for RANKL, which inhibits osteoclast differentiation and function by interrupting the interaction between RANKL and RANK, a receptor of RANKL. The identification of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) as a master transcription! factor for RANKL-induced osteoclastogenesis has provided major insight into the molecular mechanism of osteoclast differentiation. The discovery of the immunoreceptor tyrosine-based activation motif (ITAM)-mediated signals as a costimulatory signal in osteoclastogenesis has confirmed that osteoblasts play another important role in osteoclastogenesis. Mutations of RANK, OPG, and RANKL found in humans cause bone diseases associated with expected skeletal abnormalities. Thus, the RANKL/RANK/OPG axis is now recognized as the central regulator of osteoclast differentiation and function.

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  • The RANKL-activated kinase cascade requires Lys63-linked TRAF-6 auto-ubiquitination and initiates transcription of AP-1, c-Fos, NF-κB, and NFATc1, the master regulator of osteoclast differentiation.

    “This cascade requires Lys63-linked TRAF-6 auto-ubiquitination [22] and initiates the transcription of activator protein-1 (AP-1), c-Fos, NF-κB, and nuclear factor of activated T cells cytoplasmic calcineurin-dependent 1 (NFATc1), the master regulator of osteoclast differentiation [20,23,24].”

    From Osteoclasts and Microgravity (2020) · cites this paper as [23]

  • 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 [23]

  • Under the influence of the RANKL/RANK interaction, NFATc1 induces the expression of DC-STAMP, which is crucial for the fusion of osteoclast precursors.

    “Under the influence of the RANKL/RANK interaction, NFATc1 also induces the expression of DC-STAMP, which is crucial for the fusion of osteoclast precursors [91, 92].”

    From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [92]

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Authors
Kobayashi, Y., Udagawa, N., & Takahashi, N.
Affiliations
Matsumoto Dental University (JP)
ORCID
Venue
Critical Reviews™ in Eukaryotic Gene Expression
Publisher
Begell House
Published
2009
Volume
19
Issue
1
Pages
61-72
ISSN
1045-4403 (ISSN-L)
DOI
10.1615/critreveukargeneexpr.v19.i1.30
OpenAlex
W2038773004
Cited by
176
References
0
Citations by year
2026: 5 · 2025: 6 · 2024: 4 · 2023: 6 · 2022: 17 · 2021: 10 · 2020: 10 · 2019: 5 · 2018: 10 · 2017: 11 · 2016: 10 · 2015: 14 · 2014: 8 · 2013: 16 · 2012: 13
FWCI
5.88
Type
journal article
Language
en
Open access
closed
Locations
  • Critical Reviews in Eukaryotic Gene Expression (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
  • Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
Keywords
RANKL, osteoprotegerin, osteoclastogenesis, RANK, osteoblasts, NFATc1, bone resorption, bone disease, monocyte/macrophage lineage
MeSH terms
Animals, Bone and Bones, Humans, Models, Biological, Mutation, Osteoblasts, Osteoclasts, Transcription Factors, Transcription, Genetic, Protein Structure, Tertiary, Amino Acid Motifs, NFATC Transcription Factors, Mice, Osteoprotegerin, RANK Ligand

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