Overexpression of secreted frizzled-related protein 1 inhibits bone formation and attenuates parathyroid hormone bone anabolic effects
The Wnt signaling regulates many aspects of cell growth, differentiation, and death during pre- and postnatal periods, and is important for bone homeostasis. Wnt/β-catenin signaling promotes osteoblast differentiation from mesenchymal stem cells (MSCs). In differentiated osteoblasts, β-catenin signaling favours osteoprotegerin production which negatively controls osteoclast formation and subsequent bone resorption. Similarly to other growth factors, the Wnt pathway is tightly regulated by secreted or intracellular inhibitors such as secreted frizzled-related proteins (sFRPs). In vertebrates, the sFRPs consist of 7 members (sFRP1 to sFRP5, crescent and sizzled) and contain a frizzled (Fz)-related cysteine-rich domain that can bind to the Wnt proteins, thus preventing Wnt/receptor activation. Overexpression of sFRP1 in human osteoblasts accelerates osteoblast and osteocyte death. Conversely, sFRP1 deletion in mice results in resistance to age-related bone loss, decrease of osteoblast and osteocyte apoptosis, and decrease in bone anabolic response to parathyroid hormone (PTH). Thus, sFRP1 may be a potential target to control Wnt pathway and thus, bone formation.
In a recent study [1], Yao and colleagues used mice overexpressing sFRP1 to evaluate the impact of this protein on bone. These mice overexpressed sFRP1 in several tissues including bone, where sFRP1 expression was found to be 3-fold increased compared with wild-type mice. As expected, sFRP1 overexpression led to reduced Wnt/β-catenin signaling in bones. Transgenic mice developed osteopenia with trabecular bone mass reduction. Histomorphometric and biochemical analysis revealed that sFRP1 overexpression was associated with a reduction in bone formation and osteoblast activity. Accordingly, mesenchymal cells from mice overexpressing sFRP1 showed reduced osteoblast differentiation in vitro. Finally, the authors showed that, in wild-type mice, subcutaneous administration of parathyroid hormone (PTH) for 2 weeks led to an activation of Wnt/β-catenin pathway in bone. sFRP1 overexpression impaired PTH induced Wnt/β-catenin activation and blunted bone anabolic response to PTH.
This study strengthens the important function of Wnt/β-catenin signaling in osteoblasts differentiation. It also confirms a key role of this pathway in bone anabolic response to PTH.
- Yao W et al. J Bone Miner Res. 2010; 25:190-199.
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