Wnt7b Inhibits Osteoclastogenesis via AKT Activation and Glucose Metabolic Rewiring

Abstract

The imbalance between bone formation and bone resorption causes osteoporosis, which leads to severe bone fractures. It is known that increases in osteoclast numbers and activities are the main reasons for increasing bone resorption. Although extensive studies have investigated the regulation of osteoclastogenesis of bone marrow macrophages (BMMs), new pharmacological avenues still need to be unveiled for clinical purpose. Wnt ligands have been widely demonstrated as stimulators of bone formation; however, the inhibitory effect of the Wnt pathway in osteoclastogenesis is largely unknown. Here, we demonstrate that Wnt7b, a potent Wnt ligand that enhances bone formation and increases bone mass, also abolishes osteoclastogenesis in vitro. Importantly, enforced expression of Wnt in bone marrow macrophage lineage cells significantly disrupts osteoclast formation and activity, which leads to a dramatic increase in bone mass. Mechanistically, Wnt7b impacts the glucose metabolic process and AKT activation during osteoclastogenesis. Thus, we demonstrate that Wnt7b diminishes osteoclast formation, which will be beneficial for osteoporosis therapy in the future.

The role of the Wnt signalling pathway in the energy metabolism of bone remodelling

“…146 Furthermore, increased Wnt levels in cells of the macrophage lineage markedly destroy osteoclast formation and activity, resulting in a rapid increase in bone mass. 146 The mechanism is that Wnt7b affects the process of glucose metabolism and the activation of AKT during osteoclastogenesis (Table 2). 146 Wnt7b is generally expressed by the osteogenic perichondrium, which benefits the development of long bones in mice, and the deletion of Wnt7b results in delayed osteogenesis in mouse embryos.…”

“…146 The mechanism is that Wnt7b affects the process of glucose metabolism and the activation of AKT during osteoclastogenesis (Table 2). 146 Wnt7b is generally expressed by the osteogenic perichondrium, which benefits the development of long bones in mice, and the deletion of Wnt7b results in delayed osteogenesis in mouse embryos. 147,148 In contrast, the overexpression of Wnt7b in osteoblasts significantly promotes bone formation in mice.…”

“…As a potent Wnt ligand, an in vitro study showed that Wnt7b promotes bone formation, increases bone mass, and inhibits osteoclastogenesis (Figure 1 ). 146 Furthermore, increased Wnt levels in cells of the macrophage lineage markedly destroy osteoclast formation and activity, resulting in a rapid increase in bone mass. 146 The mechanism is that Wnt7b affects the process of glucose metabolism and the activation of AKT during osteoclastogenesis (Table 2 ).…”

“… 146 Furthermore, increased Wnt levels in cells of the macrophage lineage markedly destroy osteoclast formation and activity, resulting in a rapid increase in bone mass. 146 The mechanism is that Wnt7b affects the process of glucose metabolism and the activation of AKT during osteoclastogenesis (Table 2 ). 146 …”

Bioinspired sandwich-like hybrid surface functionalized scaffold capable of regulating osteogenesis, angiogenesis, and osteoclastogenesis for robust bone regeneration

“…Over the past decades, accumulated evidence has indicated that the activation of the Wnt signaling pathway is effective in enhancing bone defect healing through synergistic osteogenesis-angiogenesis regulation. Moreover, recent studies have shown that the Wnt pathway plays an indispensable role in osteoclastogenesis [ 17 , 18 ]. Specifically, Wnts can induce the expression of osteoprotegerin/osteoclastogenesis inhibitory factor (OPG/OCIF) on osteoblasts by modulating the differentiation of osteoclasts and influencing the function of osteoclasts, which also ultimately affects the bone resorption process [ 22 ].…”