Negative regulation of osteoclastogenesis by ectodomain shedding of receptor activator of NF-κB ligand.
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Receptor activator of NF-kappaB ligand (RANKL) is a transmembrane glycoprotein that has an essential role in the development of osteoclasts. The extracellular portion of RANKL is cleaved proteolytically to produce soluble RANKL, but definite RANKL sheddase(s) and the physiologic function of RANKL shedding have not yet been determined. In the present study, we found that matrix metalloproteinase (MMP) 14 and a disintegrin and metalloproteinase (ADAM) 10 have strong RANKL shedding activity. In Western blot analysis, soluble RANKL was detected as two different molecular weight products, and RNA interference of MMP14 and ADAM10 resulted in a reduction of both the lower and higher molecular weight products. Suppression of MMP14 in primary osteoblasts increased membrane-bound RANKL and promoted osteoclastogenesis in cocultures with macrophages. Soluble RANKL produced by osteoblasts from MMP14-deficient mice was markedly reduced, and their osteoclastogenic activity was promoted, consistent with the findings of increased osteoclastogenesis in vivo. RANKL shedding is an important process that down-regulates local osteoclastogenesis.
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RANKL has at least three forms, two of which possess a transmembrane domain and can be cleaved into soluble forms with osteoclast-stimulating activity.
“There are at least three forms of RANKL, two of which possess a transmembrane domain that positions the biologically active carboxy-terminus to the extracellular domain (i.e., a type II transmembrane protein) (Fig. 2).One of these forms, RANKL2, is a shorter alternative splicing variant of RANKL1 (44).Both of these variants can remain on cell surfaces or can be proteolytically cleaved into soluble”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [45]
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- Authors
- Hikita, A., Yana, I., Wakeyama, H., Nakamura, M., Kadono, Y., Oshima, Y., Nakamura, K., Seiki, M., & Tanaka, S.
- Affiliations
- The University of Tokyo (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- Corresponding author
- Tanaka, Sakae
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-12
- Volume
- 281
- Issue
- 48
- Pages
- 36846-36855
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1999201913
- Cited by
- 236
- References
- 41
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 8 · 2023: 15 · 2022: 7 · 2021: 13 · 2020: 15 · 2019: 8 · 2018: 13 · 2017: 17 · 2016: 7 · 2015: 10 · 2014: 9 · 2013: 8 · 2012: 12
- FWCI
- 6.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Keywords
- RANKL, ectodomain shedding, osteoclastogenesis, MMP-14, ADAM10, soluble RANKL, osteoblasts
- MeSH terms
- ADAM10 Protein, Animals, Binding Sites, Bone Diseases, Metabolic, Bone Marrow, Humans, Macrophages, Membrane Proteins, Mice, Inbred C57BL, Osteoblasts, Osteoclasts, Down-Regulation, Coculture Techniques, Mice, ADAM Proteins, RANK Ligand, Matrix Metalloproteinase 14, Amyloid Precursor Protein Secretases
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