Diversity Supplement: 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). The integral role of OB lineage cells in OC formation, through production of receptor activator of NF-kB ligand (RANKL) and osteoprotegrin, is well described. However, for skeletal integrity to be maintained, bone formation must be matched to resorption - that is, OC must “talk back” to OB. While the mechanism of osteoclast:osteoblast coupling is poorly understood, it is clear that dysregulation of this interaction results in bone disease. At one end of the spectrum, resorption exceeds formation resulting in the common and costly osteoporosis and fractures. At the other end of the spectrum, bone formation continues despite dysfunctional OC with very low levels of resorption, resulting in OC-rich osteopetrosis (literally, “stone bone”). This rare family of diseases is characterized by abnormally dense, osteosclerotic bone. In its autosomal recessive form, osteopetrosis is potentially fatal due to stromal cell infiltration of the bone marrow and marrow failure. The parent R21 proposal seeks to obtain critical experimental support for the hypothesis that studying dysfunctional OC:OB coupling in osteopetrosis will reveal novel molecular mechanisms driving excess bone formation and replacement of the marrow niche with OC-misdirected OB. The proposed supplement project extends the analysis of osteopetrosis models to incorporate a mouse model of the very recently identified osteopetrosis due to mutations in SLC4A2.