Claudin 11 regulates bone homeostasis via bidirectional EphB4-EphrinB2 signaling

• Published in: Experimental & molecular medicine 2018, 50(0), , pp.1-18
• Main Authors: Baek, Jong Min, Cheon, Yoon-Hee, Kwak, Sung Chul, Jun, Hong Young, Yoon, Kwon-Ha, Lee, Myeung Su, Kim, Ju-Young
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/109; 13/21; 13/51; 13/89; 14/19; 38/35; 38/77; 45/90; 631/80/304; 64/60; 692/699/2743/316/801; 96/63; 96/95; Animals; Biomedical and Life Sciences; Biomedicine; Bone growth; Bone loss; Bone Resorption - metabolism; Bone turnover; c-Fos protein; Cell Differentiation; Central nervous system; Claudins - metabolism; Ephrin-B2 - metabolism; Extracellular signal-regulated kinase; Homeostasis; Ligands; Lipopolysaccharides; Lymphocytes T; Male; Medical Biochemistry; Metabolism; Mice; Mice, Inbred ICR; Molecular Medicine; Myelin; Osteoblastogenesis; Osteoblasts - cytology; Osteoblasts - metabolism; Osteoclastogenesis; Osteoclasts - cytology; Osteoclasts - metabolism; Osteogenesis; Permeability; Phospholipase C; Phosphorylation; Protein-tyrosine kinase; Receptor, EphB4 - metabolism; Signal Transduction; Stem Cells; Tight junctions; Transcription factors; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-018-0076-3

Claudins (Cldns) are well-established components of tight junctions (TJs) that play a pivotal role in the modulation of paracellular permeability. Several studies have explored the physiologic aspects of Cldn family members in bone metabolism. However, the effect of Cldn11, a major component of central nervous system myelin, on bone homeostasis has not been reported. In this study, we demonstrate that Cldn11 is a potential target for bone disease therapeutics as a dual modulator of osteogenesis enhancement and osteoclastogenesis inhibition. We found that Cldn11 played a negative role in the receptor activator of nuclear factor kappa B ligand-induced osteoclast (OC) differentiation and function by downregulating the phosphorylated form of extracellular signal-regulated kinase (ERK), Bruton’s tyrosine kinase, and phospholipase C gamma 2, in turn impeding c-Fos and nuclear factor in activated T cell c1 expression. The enhancement of osteoblast (OB) differentiation by positive feedback of Cldn11 was achieved through the phosphorylation of Smad1/5/8, ERK, and c-Jun amino-terminal kinase. Importantly, this Cldn11-dependent dual event in bone metabolism arose from targeting EphrinB2 ligand reverse signaling in OC and EphB4 receptor forward signaling in OB. In agreement with these in vitro effects, subcutaneous injection of Cldn11 recombinant protein exerted anti-resorbing effects in a lipopolysaccharide-induced calvarial bone loss mouse model and increased osteogenic activity in a calvarial bone formation model. These findings suggest that Cldn11 is a novel regulator in bone homeostasis. Bone metabolism: A new connection Claudin 11 (Cldn11), a protein that helps form leak-proof connections between cells, also regulates bone density. Claudins are part of tight junctions, which connect cells that form barriers, such as skin cells. Some claudins have been reported to also affect bone metabolism. Ju-Young Kim and Myeung Su Lee from Wonkwang University in Iksan, South Korea, and colleagues investigated how Cldn11 affects bone metabolism. Bone undergoes constant remodeling, and the balance between new bone formation and old bone breakdown is critical. The team found that in cultured cells increasing Cldn11 increased the numbers of bone-forming cells and decreased the numbers of bone-degrading cells. In mice with experimentally induced bone weakness, injection of Cldn11 increased new bone formation and reduced bone resorption. Cldn11 provides a new target to study and t