Receptor activator of NF-κB (RANK) ligand induces ectodomain shedding of RANK in murine RAW264.7 macrophages

Akihiro Hakozaki, Masaki Yoda, Takahide Tohmonda, Mitsuru Furukawa, Tomohiro Hikata, Shinichi Uchikawa, Hironari Takaishi, Morio Matsumoto, Kazuhiro Chiba, Keisuke Horiuchi, Yoshiaki Toyama

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)


Osteoclastogenesis is a highly sophisticated process that involves a variety of membrane-bound proteins expressed in osteoblasts and osteoclast precursors. Over the past several years, proteolytic cleavage and release of the ectodomain of membrane-bound proteins, also referred to as ectodomain shedding, has emerged as an important posttranslational regulatory mechanism for modifying the function of cell surface proteins. In line with this notion, several membrane-bound molecules involved in osteoclastogenesis, including CSF-1R and receptor activator of NF-κB ligand (RANKL), are proteolytically cleaved and released from the cell surface. In this study, we investigated whether receptor activator of NF-κB (RANK), one of the most essential molecules in osteoclastogenesis, undergoes ectodomain shedding. The results showed that RANK is released in the form of a soluble monomeric protein and that TNF-α-converting enzyme is involved in this activity. We also identified potential cleavage sites in the juxtamembrane domain of RANK and found that rRANKL induces RANK shedding in a macrophage-like cell line RAW264.7 via TNFR-associated factor 6 and MAPK pathways. Furthermore, we found that RANKL-induced osteoclastogenesis is accelerated in TNF-α-converting enzyme-deficient osteoclast precursors. These observations suggest the potential involvement of ectodomain shedding in the regulation of RANK functions and may provide novel insights into the mechanisms of osteoclastogenesis.

Original languageEnglish
Pages (from-to)2442-2448
Number of pages7
JournalJournal of Immunology
Issue number5
Publication statusPublished - 2010 Mar 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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