Molecular Bases of the Regulation of Bone Remodeling by the Canonical Wnt Signaling Pathway

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Osteoporosis is a common, prevalent, and debilitating condition, particularly in postmenopausal women. Genetics play a major role in determining peak bone mass and fracture risk, but few genes have been demonstrated conclusively to be involved, much less the signaling pathways with which they are affiliated. The identification of mutations in the gene Lrp5, a Wnt coreceptor, as the cause for both osteoporotic and high‐bone mass disorders implicated the canonical Wnt signaling pathway in bone mass regulation. Since Lrp5, other Wnt components have been identified as being regulators of bone mass, and Wnt target genes affecting bone homeostasis have begun to be elucidated. This chapter looks at the various components of the canonical Wnt signaling pathway and the data indicating that this pathway plays a major role in the control of both bone formation and bone resorption, the two key aspects of bone remodeling.

Introduction

There are two specific cell types responsible for maintenance of a constant bone mass: osteoblasts that are the bone‐forming cells, and osteoclasts that are the bone‐resorbing cells. The osteoblast, a cell of mesenchymal origin, synthesizes proteins of the extracellular matrix (ECM) and, as such, is responsible for bone formation. It also expresses genes that are necessary and sufficient for the mineralization of this ECM and, thirdly, controls osteoclast differentiation. The osteoclast, on the other hand, has only one main function: bone resorption. Thus, a hierarchy exists within the bone milieu where the osteoblast not only fulfils a greater number of functions than the osteoclast, but also is able to regulate the osteoclast itself.

In vertebrates, a process called bone remodeling takes place, which is required in order to maintain a constant bone mass. There is first a phase of resorption by the osteoclasts, which occurs simultaneously at numerous sites within the skeleton and occurs relatively quickly, that is, about 3 weeks per site. This resorptive phase is followed by the rebuilding of bone by the osteoblasts, which in contrast lasts over 3 months per site. These two phases must remain in balance to achieve homeostasis and a constant bone mass. Any increase or decrease in proliferation or activity of either cell type can lead to aberrant changes in bone mass. Thus, bone remodeling is necessarily dysregulated in an osteoporotic (low bone mass) or osteopetrotic (high bone mass) state.

In young adults and in premenopausal women, bone resorption and bone formation occur at the same rate, therefore bone mass is maintained over time. Whether due to menopause or aging, over time there is a relative increase in bone resorption, leading to bone loss and osteoporosis (Riggs et al., 1998). Both bone formation and bone resorption are subject to regulation, either by local factors secreted by bone cells themselves or systemically by hormones.

At the local level, two positive and one negative regulators of osteoclast differentiation have been identified. M‐Csf (macrophage colony stimulating factor) and the receptor activator of NF‐κB ligand (Rankl) have been demonstrated to be necessary and sufficient for osteoclast differentiation and function (Lacey 1998, Wong 1999, Yasuda 1998, Yoshida 1990). These two factors are secreted by osteoblasts, as is a third factor that inhibits osteoclast differentiation. Osteoprotegerin (Opg) encodes a soluble decoy receptor for Rankl, thereby preventing osteoclast differentiation (Simonet et al., 1997). Thus, there are both activators and inhibitors of osteoclast differentiation being secreted by the osteoblast.

At the systemic level a number of signaling pathways have been characterized to influence bone remodeling. The insulin‐like growth factor family has been shown to stimulate Type I collagen gene expression (Schmid et al., 1989) and stimulate osteoblast proliferation in vitro (Canalis, 1993). Meanwhile the bone morphogenetic protein (BMP) family, a subset of the transforming growth factor β (TGFβ) superfamily, has been shown to induce ectopic bone formation in vitro and indirect evidence links them to bone mass regulation in vivo (Mundy 1999, Reddi 1997, Yoshida 2000). A third signaling family that has been shown to influence bone remodeling is the Wnt signaling pathway.

Section snippets

Canonical Wnt Signaling

The Wnt family of secreted factors is involved in numerous aspects of cellular biology, ranging from cell fate determination, polarity and differentiation to migration, proliferation, and function (Moon et al., 2002). With regards to skeletal biology, Wnts are involved in a variety of processes: from limb patterning and formation to chondrogenesis as well as osteoblast and osteoclast differentiation and function. This chapter will focus mostly on the role of the Wnt signaling pathway in bone

Other Wnt Signaling Molecules

A plethora of data now exists regarding the roles of Lrp5/6 and β‐catenin/Lef/Tcf signaling in bone remodeling. However, the information regarding Wnt signaling in bone is by no means limited to these proteins. There are a number of components of the canonical Wnt signaling pathway that have also been characterized to play important roles in bone biology, in vitro and in vivo. Other components of canonical Wnt signaling will now be discussed regarding their effects on bone remodeling.

Secreted Wnt Inhibitors and Agonists

There are a number of different secreted protein families that antagonize the canonical Wnt signaling pathway, which can be subdivided into two different classes. Some Wnt inhibitors bind to the Lrp5/6 receptor and thereby prevent formation of Wnt‐Fzd‐Lrp complex. Dkks, Wise, and Sclerostin fall into this first category. The second group interacts with either Wnts and/or Fzds and inhibit interactions between these two proteins; this group includes Sfrps, Cerberus, and Wif‐1. Studies concerning

Kremens

Kremens (Kringle‐coding genes marking the eye and the nose; Krms) are single transmembrane receptors that interact with Dkk and Lrp6 to inhibit canonical Wnt signaling (Mao 2002, Nakamura 2001). A trimer complex formed between Krm, Dkk, and Lrp6 is removed from the cell surface via endocytosis and Lrp6 is either recycled or degraded. This Krm‐Dkk‐Lrp6 interaction, therefore, removes Wnt coreceptors from the cell surface and inhibits canonical Wnt signaling (Mao et al., 2002). Presumably, Lrp5

Conclusions and Future Work

Wnt signaling controls fate determination, differentiation, proliferation, survival and function, as well as osteoclast differentiation, within osteoblasts. The regulation of both cell types by canonical Wnt signaling exemplifies the diversity of target genes this signaling pathway possesses. Lrp and β‐catenin‐dependent signaling show how dysregulation of two components of the same pathway can give rise to the same results through completely different etiologies. The roles of other components

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