Plotkin, Lilian I.Shimonty, AnikaBonewald, Lynda F.Brault, JeffRobling, Alexander G.White, Kenneth E.2023-08-162023-08-162023-07https://hdl.handle.net/1805/34937Indiana University-Purdue University Indianapolis (IUPUI)Irisin is a myokine generated when Fibronectin type III Domain Containing protein 5 (FNDC5) is proteolytically cleaved during exercise. While irisin has been shown to be beneficial in the functions of the brain, heart, and adipose tissue, its effect on bone cells remains contradictory. Osteocytes are the most abundant and longest-living bone cells, with different transcriptomes based on sex and age. One of the major functions of osteocytes is osteocytic osteolysis, the removal of their perilacunar matrix. A previous study showed that irisin deletion protects bone from ovariectomy-induced loss due to less osteoclastic resorption and less osteocytic osteolysis. Therefore, we hypothesized that FNDC5/irisin modulates the osteocyte function of osteocytic osteolysis in a sex-dependent manner. Under normal conditions, there was no difference in bone parameters between wildtype and FNDC5-null adult female mice starting from 5 to 20 months of age. However, 5-month-old null male mice had higher bone mass, but weaker bone compared to wildtype males, which persisted up to 20 months. Both 5-month-old female and male null mice had significantly lower TRAP-positive osteocytes, suggesting a role of irisin in priming the osteocytes for bone resorption. Osteocytes from female wildtype mice show higher lacunar area and upregulated resorption genes compared to wildtype males. However, null females and null males do not have significant differences in the lacunar area or resorption genes. Under calcium-deficient conditions, both 5 and 18-month-old female null mice lost less bone compared to their wildtype counterparts. In contrast, both 5 and 18-month-old null male mice lost more bone than age-matched wildtype males. Additionally, the percentage of bone loss was greater in the aged null male mice compared to 5-month-old null males. In summary, in female osteocytes, irisin works to release calcium from bone during lactation, ensuring offspring survival; however, with aging and hypocalcemia, irisin exerts a negative effect on bone mass. In contrast, irisin works to maintain bone mass and strength by modulating male osteocyte function. This study is the first to demonstrate a sex and age-specific irisin effect on the osteocyte function of osteocytic osteolysis, which has implications for the development of osteoporosis treatment.en-USThesis