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 been regarded as defects in osteoblast function, the role of matrix-embedded osteocytes in OI pathogenesis remains largely unknown. Homozygous human SP7 (c.946 C > T, R316C) mutation results in a recessive form of OI characterized by fragility fractures, low bone mineral density and osteocyte dendrite defects. To better understand how the OI-causing R316C mutation affects the function of SP7, we generated Sp7^R342C knock-in mice. Consistent with patient phenotypes, Sp7^R342C/R342C mice demonstrate increased cortical porosity and reduced cortical bone mineral density. Sp7^R342C/R342C mice show osteocyte dendrite defects, increased osteocyte apoptosis, and intracortical bone remodeling with ectopic intracortical osteoclasts and elevated osteocyte Tnfsf11 expression. Remarkably, these defects in osteocyte function contrast to only mild changes in mature osteoblast function, suggesting that this Sp7 mutation selectively interferes with the function of Sp7 in osteocytes and mature osteoblasts, but not during early stages of osteoblast differentiation. Osteocyte morphology changes in Sp7^R342C/R342C mice were not restored by inhibiting osteoclast formation, indicating that dendrite defects lie upstream of high intracortical 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 supports a model in which osteocyte dysfunction can drive OI pathogenesis and provides a valuable resource to test novel therapeutic approaches and to understand the osteocyte-specific role of SP7 in bone remodeling.