Osteogenesis imperfecta (OI) is an inherited disorder characterized by severe osteopenia, bone fragility, and high fracture risk. OI patients during growth often exhibit high bone turnover with the net result of low bone mass. Besides being abnormally fragile, OI bones have increased osteocyte density which may result in a disruption of osteocyte function. Recent evidence shows that osteocytes can significantly affect bone remodeling under physiological and pathological conditions through production of signaling molecules and/or modulation of signaling pathways. These include RANKL, an essential cytokine for osteoclastogenesis, and WNT signaling which is important for osteoblast differentiation and maturation. Importantly, it was shown that osteocyte-derived RANKL is a critical mediator of bone loss caused by ovariectomy, low-calcium diet, unloading and glucocorticoid treatment. I hypothesized that osteocytes become dysregulated in OI, affecting signaling pathways critical for bone homeostasis, and that osteocyte-derived RANKL contributes to the low bone mass and high bone turnover OI phenotype. In aim 1, I used RNA sequencing as an unbiased way to explore dysregulation of the osteocyte transcriptome in 2 different OI mouse models. My data showed that osteocytes transcription is greatly dysregulated in OI, including transcripts involved in WNT signaling, ECM production, and many other facets of cell biology. In aim 2, I crossed the oim/oim mouse model of OI and a mouse with osteocyte-targeted RANKL deletion. The loss of RANKL in osteocytes in oim/oim mice (oim-RANKL-cKO) resulted in dramatically increased cancellous bone mass in both the femur and lumbar spine, increased vertebral cortical thickness, but no significant changes in ultimate bone strength in femur or spine. Furthermore, unlike previous reports, oim/oim mice did not exhibit high bone turnover and their low bone mass was due to defective bone formation and not increased bone resorption. The loss of osteocyte-derived RANKL further diminished bone resorption and formation in oim-RANKL-cKO compared to oim/oim. In summary, for the first time I have shown that the osteocyte transcriptome is dysregulated in OI, including signaling pathways that are known to affect bone remodeling processes, and that osteocyte-produced RANKL contributes significantly to the low bone mass observed in OI.