Clinical assessment of fracture risk and novel therapeutic strategies to combat osteoporosis  Mark S. Nanes, M.D., Ph.D., Caleb B. Kallen, M.D., Ph.D.  Fertility and Sterility  Volume 92, Issue 2, Pages 403-412 (August 2009) DOI: 10.1016/j.fertnstert.2009.05.049 Copyright © 2009 American Society for Reproductive Medicine Terms and Conditions

Figure 1 Wnt pathways regulating osteoblastogenesis and osteoblast activity. In the basal state, low-level Wnt expression or inhibition of Wnt binding to membrane receptors leads to degradation of β-catenin and inactivation of the signaling cascade (A). Wnt signaling through the Wnt receptor, frizzled, and coreceptors, LRP5 or LRP6, will lead to the activation of Disheveled, which in turn inhibits the phosphorylation activity of GSK-3β, leading ultimately to enhanced levels of intracellular and intranuclear β-catenin (B). Once in the cell nucleus, β-catenin binds and activates the T cell factor (TCF) and lymphoid-enhancing factor (LEF) transcription factors. The formation of the heterodimeric β-catenin-TCF/LEF is important for the activation of gene transcription from osteoblast genes such as Runx2 and Osterix (Osx). Wnt pathways also inhibit adipogenic gene expression (see text). Wnt signaling can be inhibited by the Wnt-receptor/coreceptor-bound antagonists, which include sclerostin, DKK-1, and secreted frizzled-related protein-1 (sFRP-1). Also shown is a novel serotonin- (5-HT)-regulated pathway, which appears to negatively regulate osteoblast proliferation through the transcription factor CREB. Fertility and Sterility 2009 92, 403-412DOI: (10.1016/j.fertnstert.2009.05.049) Copyright © 2009 American Society for Reproductive Medicine Terms and Conditions

Figure 2 Pathways of osteoclastogenesis and regulators of osteoclast activity. Bone homeostasis is maintained by a balance between bone-forming cells, the osteoblasts (OBs), and bone-resorbing cells, the osteoclasts (OCs). When receptor activator of NFκB (RANK)-expressing OC precursor cells are exposed to increasing concentrations of the RANKL, they undergo differentiation into mature osteoclasts. This process is facilitated by additional mesenchymal stem cell and activated T-cell products including M-CSF and TNFα, respectively, the latter of which is upregulated under conditions of estrogen depletion (A). With prolonged estrogen depletion, the activated T cells will stimulate osteoclastogenesis directly, via the secretion of soluble RANKL (sRANKL) and TNFα, and also indirectly, by stimulating the expression of the cell surface RANKL and the secretion of M-CSF by osteoblasts and stromal cells. Under basal conditions (B), OC formation is negatively regulated by osteoprotegerin (OPG), a soluble decoy ligand for RANK. Under such conditions, T cells may contribute directly or indirectly to the inhibition of osteoclastogenesis by stimulating B cell and OB expression of OPG. Fertility and Sterility 2009 92, 403-412DOI: (10.1016/j.fertnstert.2009.05.049) Copyright © 2009 American Society for Reproductive Medicine Terms and Conditions