Talking Back: leveraging dysfunctional osteoclasts to identify novel pathways of osteoclast-osteoblast communication

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PROJECT SUMMARY Proper bone structure relies on a complex interplay of molecular signals between bone resorbing osteoclasts (OCs) and bone forming osteoblasts (OBs). For skeletal integrity to be maintained, bone formation must match resorption—that is OC must “talk back” to OB. This coupling requires recruitment of osteoprogenitors onto the resorption surface. This process is perturbed in osteopetrosis (literally, “stone bone”), where bone formation continues despite dysfunctional OC with very low levels of resorption. The signals coupling resorption to formation are not fully understood, but appear to require OC. We describe two new mouse models of dysregulated coupling. Mice with conditional deletion of Nfatc1, the key driver of the OC transcriptional program, in mature OC (Ctks-Cre;Nfatc1fl/fl, henceforth Nfatc1DOC) have accumulation of proliferating RUNX2+, alkaline phosphatase-expressing osteoblastic precursors in their marrow. Mutant OC are both necessary and sufficient for this osteoblastic precursor expansion. We observe a similar phenomenon in Slc4a2-/- mice, a model of bovine osteopetrosis. Our conceptual innovation is that dysregulated coupling contributes to osteosclerosis in the settings of dysfunctional OC. This concept leads to our overarching hypothesis that, despite disparate underlying genetic lesions, dysfunctional OC in Nfatc1DOC mice share a common molecular derangement of the coupling process with mouse and zebrafish models of osteopetrosis. In Aim 1, we propose transcriptomic analysis to identify differentially regulated OC-specific transcripts common to these models as candidate mediators of OC:OB communication. In Aim 2, we test the specific hypothesis that hematologic impairment in osteopetrosis is caused by OC-dependent obliteration of the marrow space by osteoblastic precursors, using mouse models and human biopsy samples from individuals with osteopetrosis to validate our hypothesis in vivo. These studies leverage technical innovations including the isolation of pure populations of primary OC and advanced molecular bone histology techniques to interrogate gene expression and are supported by an outstanding team of collaborators with expertise in OC biology (Dr. Charles), zebrafish genetics and skeletal development (Dr. Henke), molecular bone histology (Dr. Andersen), and bioinformatic expertise (Center for Skeletal Research bone sequencing core run by Dr. Warman). This work will provide insight into normal OC:OB coupling during bone remodeling, with the potential to identify new therapeutic targets for bone diseases where coupling is either inappropriately low (osteoporosis) or inappropriately high (osteopetrosis).