The regulation of osteoclast differentiation by Wnt signals

Abstract

Wnt ligands activate β-catenin-dependent canonical and -independent noncanonical signaling pathways. Wnt regulates many physiological events such as the development of organs and bone metabolism. In contrast, failed signaling leads to pathological conditions including cancer and osteoporosis. Analyses of loss-of-function mutations in the low-density lipoprotein receptor-related protein (Lrp) 5 gene revealed that Lrp5 acted as a co-receptor of Wnt/β-catenin signals and positively regulated bone mass in humans and mice. Many players in Wnt signals including sclerostin, an osteocyte-derived Wnt antagonist, also have since been found to influence bone mass. Bone mass is regulated by the activities of bone-forming osteoblasts, -resorbing osteoclasts and matrix-embedded osteocytes. The roles of Wnt/β-catenin signals in osteoblastogenesis and osteoclastogenesis have been established by the findings of a large number of in vitro and in vivo studies. In contrast, the roles of noncanonical Wnt signals in bone metabolism are only now being examined. In this review, we introduced and discussed recent information on the roles of Wnt signals in bone resorption.

Figure 1

Roles of Wnt/β-catenin signals in osteoclast differentiation. (a) In the absence of Wnt ligands, the β-catenin destruction complex phosphorylated β-catenin. Phosphorylated β-catenin is degraded by the ubiquitin-proteasome pathway. (b) Binding of Wnt ligands with the receptor complex of frizzled and Lrp5/6 inactivates the β-catenin destruction complex, which, in turn, induces the cytosolic accumulation and nuclear translocation of β-catenin. Nuclear β-catenin with Tcf1 induces the transcription of the Tnfrsf11b gene. Sclerostin, an osteocyte-derived inhibitor, inhibits Wnt/β-catenin signals. Lrp4 facilitates the inhibitory action of sclerostin.

Figure 2

Effects of Wnt16 through osteoblasts on osteoclast differentiation. Wnt16 activates Wnt/β-catenin signals in osteoblasts, which, in turn, induces the expression of osteoprotegerin. Osteoprotegerin interferes the binding of Rankl with Rank and inhibits osteoclast differentiation.

Figure 3

Roles of noncanonical Wnt signals in osteoclast differentiation. Wnt5a secreted from osteoblasts binds to Ror2 in osteoclast precursors. Ror2-mediated signals promote the expression of Rank in the precursors, thereby enhancing Rankl-induced osteoclast differentiation. Wnt4 and Wnt16 are also secreted from osteoblasts and inhibit the Rankl-induced activation of NF-κB and NFATc1 signals, which, in turn, inhibit osteoclast differentiation.