Osteoclast-independent osteocyte dendrite defects in mice bearing the Osteogenesis Imperfecta-causing Sp7 R342C mutation

Osteogenesis imperfecta (OI) is a group of diseases caused by defects in type I collagen processing which result in skeletal fragility. While these disorders have traditionally been regarded as defects in osteoblast function, the role of matrix-embedded osteocytes, descendants of osteoblasts, in OI pathogenesis remains unknown. The homozygous human SP7 (c.946C > T, R316C) mutation results in a recessive form of osteogenesis imperfecta characterized by short stature, fragility fractures, low bone mineral density, and osteocyte dendrite defects. To better understand how the osteogenesis imperfecta-causingSP7 R316Cmutation affects the function of this transcription factor in different osteoblast lineage cells in bone, we generatedSp7 R342Cknock-in mice. Homozygous mutantSp7 R342C/R342Cmice demonstrate increased cortical porosity and reduced cortical bone mineral density, findings consistent with phenotypes observed in patients with this mutation. Sp7 R342Cmice show osteocyte dendrite defects, increased osteocyte apoptosis, and intracortical bone remodeling characterized by ectopic intracortical osteoclasts and elevated Tnfsf11 expression by osteocytes. Remarkably, these overt defects in osteocyte function contrast to preserved osteoblast function, suggesting that this Sp7 point mutation selectively interferes with the function of this transcription factor in osteocytes but not osteoblasts. Osteocyte morphology changes in Sp7 R342C/R342Cmice were not restored by inhibiting osteoclast formation, indicating that dendrite defects lie upstream of high intra-cortical osteoclast activity in this model. Moreover, transcriptomic profiling reveals that the expression of a core set osteocyte-enriched genes is highly dysregulated by the R342C mutation. Thus, this model supports a model in which osteocyte dysfunction can drive osteogenesis imperfecta pathogenesis, and provides a valuable resource to test novel therapeutic approaches and to understand the osteocyte-specific role of SP7 in bone homeostasis and remodeling.