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Measuring G-protein-coupled Receptor Signaling via Radio-labeled GTP Binding
Published on: June 9, 2017
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WAIF1 Is a Cell-Surface CTHRC1 Binding Protein Coupling Bone Resorption and Formation
Kazuhiko Matsuoka1, Yukihiro Kohara1, Yoshinori Naoe1
1Department of Bone and Joint Disease, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.
Summary
Osteoclast protein CTHRC1 binds WAIF1 on stromal cells, activating a novel pathway that links bone resorption to formation. This discovery reveals a key mechanism in bone remodeling and mass regulation.
Area of Science:
- Bone Biology
- Cell Signaling
- Molecular Mechanisms
Background:
- Osteoclast-derived CTHRC1 (collagen triple helix repeat containing 1) promotes osteoblast differentiation.
- The precise molecular mechanisms underlying CTHRC1's function in bone remodeling are not fully understood.
Purpose of the Study:
- To elucidate the mechanism by which CTHRC1 stimulates osteoblast differentiation.
- To identify the cell-surface protein that interacts with CTHRC1.
- To investigate the role of this interaction in bone remodeling.
Main Methods:
- Identified CTHRC1-binding protein using co-immunoprecipitation and mass spectrometry.
- Analyzed gene expression patterns of CTHRC1 and its binding partner (Tpbg).
- Utilized cell culture models (marrow stromal cells) and in vivo mouse models with genetic deletions (osteoblast lineage-specific Tpbg deletion).
- Assessed alkaline phosphatase activity, protein signaling pathways (PKCδ, MEK/ERK), Rankl expression, bone formation, and bone resorption.
Main Results:
- Wnt-activated inhibitory factor 1 (WAIF1), also known as 5T4, was identified as a cell-surface protein that binds CTHRC1.
- The gene encoding WAIF1, Trophoblast glycoprotein (Tpbg), is highly expressed in bone and brain, similar to Cthrc1.
- Downregulation of Tpbg in marrow stromal cells impaired CTHRC1 binding and CTHRC1-stimulated osteoblast differentiation via the WAIF1/PKCδ/ERK pathway.
- Osteoblast lineage-specific deletion of Tpbg led to reduced Rankl expression, impaired bone formation and resorption, and hindered bone mass recovery after resorption, mimicking osteoclast-specific Cthrc1 deficiency.
Conclusions:
- CTHRC1 binding to WAIF1 on stromal cells activates the PKCδ-ERK signaling pathway, promoting osteoblast differentiation.
- This interaction represents a novel molecular link between bone resorption and formation during bone remodeling.
- The CTHRC1-WAIF1 axis plays a critical role in regulating bone mass and coupling bone resorption with formation.
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