The Effects of FNDC5/Irisin on Osteocyte Functions

Indiana 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.2025-08-1

Deletion of FNDC5/Irisin modifies murine osteocyte function in a sex-specific manner

Irisin, released from exercised muscle, has been shown to have beneficial effects on numerous tissues but its effects on bone are unclear. We found significant sex and genotype differences in bone from wildtype (WT) mice compared to mice lacking Fndc5 (KO), with and without calcium deficiency. Despite their bone being indistinguishable from WT females, KO female mice were partially protected from osteocytic osteolysis and osteoclastic bone resorption when allowed to lactate or when placed on a low-calcium diet. Male KO mice have more but weaker bone compared to WT males, and when challenged with a low-calcium diet lost more bone than WT males. To begin to understand responsible molecular mechanisms, osteocyte transcriptomics was performed. Osteocytes from WT females had greater expression of genes associated with osteocytic osteolysis and osteoclastic bone resorption compared to WT males which had greater expression of genes associated with steroid and fatty acid metabolism. Few differences were observed between female KO and WT osteocytes, but with a low calcium diet, the KO females had lower expression of genes responsible for osteocytic osteolysis and osteoclastic resorption than the WT females. Male KO osteocytes had lower expression of genes associated with steroid and fatty acid metabolism, but higher expression of genes associated with bone resorption compared to male WT. In conclusion, irisin plays a critical role in the development of the male but not the female skeleton and protects male but not female bone from calcium deficiency. We propose irisin ensures the survival of offspring by targeting the osteocyte to provide calcium in lactating females, a novel function for this myokine

Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant multisystemic vascular dysplasia, characterized by arteriovenous malformations (AVMs), mucocutaneous telangiectasia and nosebleeds. HHT is caused by a heterozygous null allele in ACVRL1, ENG, or SMAD4, which encode proteins mediating bone morphogenetic protein (BMP) signaling. Several missense and stop-gain variants identified in GDF2 (encoding BMP9) have been reported to cause a vascular anomaly syndrome similar to HHT, however none of these patients met diagnostic criteria for HHT. HHT families from UK NHS Genomic Medicine Centres were recruited to the Genomics England 100,000 Genomes Project. Whole genome sequencing and tiering protocols identified a novel, heterozygous GDF2 sequence variant in all three affected members of one HHT family who had previously screened negative for ACVRL1, ENG, and SMAD4. All three had nosebleeds and typical HHT telangiectasia, and the proband also had severe pulmonary AVMs from childhood. In vitro studies showed the mutant construct expressed the proprotein but lacked active mature BMP9 dimer, suggesting the mutation disrupts correct cleavage of the protein. Plasma BMP9 levels in the patients were significantly lower than controls. In conclusion, we propose that this heterozygous GDF2 variant is a rare cause of HHT associated with pulmonary AVMs