Wnt4 signaling prevents skeletal aging and inflammation by inhibiting nuclear factor-κB

Yu et al. Nat, Med. 2014; 20: 1009-17

Speaker: Guan-Yu Chen (陳冠宇)             Time: 15:00~16:00, Dec. 24, 2014

Commentator: Dr. Yu-Hsiang Hsu (許育祥)     Place: Room 601

Abstract:

Osteoporosis, resulting from inhibited bone formation and induced bone resorption, is associated with aging, hormonal deficiency, and chronic inflammation [1]. Wnt signaling plays an important role not only in embryonic development but also in bone homeostasis. Although the roles of canonical Wnt signaling have been well studied in bone metabolism, the role of noncanonicalWnt signaling is poorly known in bone formation and resorption. Wnt4 was shown to promote osteoblast differentiation of mesenchymal stem cells [2]. In this study, the authors generated transgenic (TG) mice expressing Wnt4 from osteoblasts to investigate the therapeutic potential of Wnt4. In vivo, Wnt4 Tg mice exhibited significantly higher levels of bone mineral density (BMD) and bone volume/tissue volume ratio (BV/TV) compared with wild-type (WT) mice, suggesting that Wnt4 can enhance bone formation. In addition, the effects of Wnt4 were studied in three models of bone loss, including ovariectomy, chronic inflammation, and aging. In these models, osteoblast counts and bone formation rates were higher and osteoclast counts were lower in Wnt4 TG mice than in WT mice. Serum concentrations of osteocalcin were higher, whereas those of Trap5b, tumor necrosis factor, and interleukin-6 were lower in Wnt4 TG mice than in WT mice. These pieces of evidence reveal that Wnt4 provides protection against bone loss and inflammation. Mechanistically, Wnt4 could inhibit NF-κB activation by suppressing TGF-β-activated kinase-1 (Tak1) phosphorylation and interfering with Tak1-Traf6 binding in macrophages and osteoclast precursors. In conclusion, Wnt4 may be a potential target for treating skeletal aging and inflammatory bone diseases.

References:

1.  Chang, J. et al. Inhibition of osteoblastic bone formation by nuclear factor-κB. Nat. Med. 2009; 15: 682-9.

2.  Chang, J. et al. Noncanonical Wnt-4 signaling enhances bone regeneration of mesenchymal stem cells in craniofacial defects through activation of p38 MAPK. J. Biol. Chem. 2007; 282: 30938-48.