eLife assessment
The study presents valuable findings on sexually dimorphic patterns of osteocytic transcriptomes and low calcium diet-induced osteocytic osteolysis in FNDC5-deficient mice. The authors present solid evidence for sex-specific changes in osteocyte morphology and gene expression under a calcium-demanding setting in this particular strain of mice, although the protective role of FNDC5-deficiency in lactation and low-calcium diet in female mice remains unclear due to lack of mechanistic studies. The study also lacks evidence that irisin, a proteolytically cleaved product of FNDC5, is responsible for the observed phenotypes, as irisin was not directly measured.