Osteocytes contribute to sex-specific differences in osteoarthritic pain

Osteoarthritic (OA) pain affects 18% of females and 9.6% of males aged over 60 worldwide, with 62% of all OA patients being women. The molecular drivers of sex-based differences in OA are unknown. Bone is intricately coupled with the sensory nervous system and one of the only joint tissues known to show changes that correlate with patient pain in OA. There are fundamental sex differences in pain sensation and bone biology which may be intrinsic to OA disease progression, however these differences are vastly under researched. We have utilised three data sets to investigate the hypothesis that potential mediators responsible for sex dependent pain mechanisms displayed in OA are derived from mechanically stimulated osteocytes. Our published dataset of the <i>in vitro</i> human osteocyte mechanosome was independently compared with published data from, sex-based gene expression differences in human long bone, the sex-based gene expression differences during the skeletal maturation of the mouse osteocyte transcriptome and sex specific OA risk factors and effector genes in a large human GWAS. 80 of the 377 sex-specific genes identified in the mouse osteocyte transcriptome were mechanically regulated in osteocytes with enrichment associated with neural crest migration and axon extension, and DISEASES analysis enrichment for the rheumatoid arthritis pathway. 3861 mechanically regulated osteocytic genes displayed sex-specific differences in human long bone with enrichment for genes associated with the synapse, sensory perception of pain, axon guidance, immune responses, distal peripheral sensory neuropathy, sensory neuropathy, and poor wound healing. 32 of 77 effector genes and 1 of 3 female specific OA risk factor genes identified in the human GWAS were differentially expressed in the osteocyte mechanosome and male and female bone. This analysis lends support to the hypothesis that mechanically regulated genes in osteocytes could influence sex specific differences in osteoarthritic pain and highlights pain pathways with approved drugs that could potentially treat elevated pain susceptibility in females with OA.