In this series, the Review article by Ormond MacDougald andcolleagues (41) focuses on the role of Wnt signaling in osteoblastformation and function. Wnts, a family of secreted glycoproteinswith multiple inhibitors, are ligands for the family of 7-membrane–spanningfrizzled receptors and play a prominent role in both the earlyand later stages of osteoblast differentiation. Wnt antagonistsinclude Dickkopfs (Dkks) and secreted frizzled-related proteins(sFRPs). While their signaling pathways were characterized originallyin terms of development, Wnts regulate numerous cellular functionsand have been linked recently to cancer and stem cell biology.It is also clear that individual Wnts utilize canonical andnoncanonical pathways (42); the endogenous Wnt ligands in boneremain unidentified, although Wnt10b was recently implicatedby MacDougald et al. (43). The canonical pathway is well establishedand involves Wnt-dependent inhibition of proteasome-mediateddegradation of ß-catenin, which forms complexes withmembers of the T cell factor/lymphoid enhancer binding factor(TCF/LEF) family that regulate transcription when it accumulatesin the nucleus. The noncanonical pathway, also frizzled dependent,activates different intracellular signals including the calcium-calmodulin-PKCaxis and the Rho family of small GTPases.
MacDougald and colleagues review the current information onWnts and bone biology. The story began with the identificationof loss- and gain-of-function mutations in LDL receptor–relatedprotein 5 (LRP5), a frizzled coreceptor, that correlate withchanges in human bone mass. More recent studies showed thatß-catenin, which is downstream of the Wnt–LRP5/6–frizzledaxis, is indispensable for osteoblast differentiation in themouse (44). Several papers cited by MacDougald et al. are worthyof comment here. Whereas mice lacking frizzled-related protein1 have increased bone mass arising from markedly decreased osteoblastapoptosis, and Lrp5–/– mice exhibit a predominantdeficit in osteoblast number and function, Col1-Cre; ß-cateninc/canimals show mainly a secondary defect in osteoclasts. Theseresults may reflect different modes of Wnt signaling: canonicalversus noncanonical pathways, Wnt-dependent versus -independentsignaling, or unique roles for different Wnt family members.Identification of downstream targets of Wnt signaling is anunderexplored subject: osteoprotegerin (OPG) was identifiedas a direct target in osteoblasts, and the anabolic genes subjectto Wnt regulation are not known but may include BMPs. Despitethe implied importance of canonical Wnt signaling in osteoblastbiology, the role of the TCF/LEF family of transcription factorsis unclear. Since ß-catenin participates in transcriptionalcomplexes with molecules other than TCF/LEFs, some target genesmay not be regulated via TCF/LEF binding sites. Finally, MacDougaldet al. may understate the problem of targeting glycogen synthasekinase 3 (GSK3), a downstream effector of Wnt/ß-cateninsignaling and a molecule for which a number of potent inhibitorshave been developed (45). As pointed out, long-term treatmentwith GSK3 inhibitors may predispose cells to an oncogenic mutation.On the other hand, lithium ions, a nonspecific inhibitor ofGSK3, have been used for decades without apparent problems inthis regard (45).