Irisin deficiency disturbs bone metabolism

Abstract

Balancing the process of bone formation and resorption is important in the maintenance of healthy bone. Therefore, the discovery of novel factors that can regulate bone metabolism remains needed. Irisin is a newly identified hormone-like peptide. Recent studies have reported the involvement of irisin in many physiological and pathological conditions with bone mineral density changes, including osteopenia and osteoporotic fractures. In this study, we generated the first line of Osx-Cre:FNDC5/ irisin KO mice, in which FNDC5/irisin was specifically deleted in the osteoblast lineage. Gene and protein expressions of irisin were remarkably decreased in bones but no significant differences in other tissues were observed in knockout mice. FNDC5/irisin deficient mice showed a lower bone density and significantly delayed bone development and mineralization from early-stage to adulthood. Our phenotypical analysis exhibited decreased osteoblast-related gene expression and increased osteoclast-related gene expression in bone tissues, and reduced adipose tissue browning due to bone-born irisin deletion. By harvesting and culturing MSCs from the knockout mice, we found that osteoblastogenesis was inhibited and osteoclastogenesis was increased. By using irisin stimulated wildtype primary cells as a gainof-function model, we further revealed the effects and mechanisms of irisin on promoting osteogenesis and inhibiting osteoclastogenesis in vitro. In addition, positive effects of exercise, including bone strength enhancement and body weight loss were remarkably weakened due to irisin deficiency. Interestingly, these changes can be rescued by supplemental administration of recombinant irisin during exercise. Our study indicates that irisin plays an important role in bone metabolism and the crosstalk between bone and adipose tissue. Irisin represents a potential molecule for the prevention and treatment of bone metabolic diseases.

Progress and Challenges in the Biology of FNDC5 and Irisin

“…Both groups ( 26 , 75 ) note that their results—that irisin inhibits bone formation—are the opposite of Colaianni et al ( 114 , 122 ). They did not reference the results of other groups who also found irisin enhanced bone formation ( 120 , 124 , 125 ). Estell et al ( 75 ) suggested that the opposite effects of irisin (inhibition vs enhancement of bone formation) might be due to the concentration of irisin and the duration or frequency of application.…”

“…In another recent study, Zhu et al ( 125 ) performed a selective KO of FNDC5 in bone cells using an osterix-Cre driver. Osterix-Cre has been used to knock out genes specifically in osteoblasts and osteocytes.…”

Irisin Mitigates Oxidative Stress, Chondrocyte Dysfunction and Osteoarthritis Development through Regulating Mitochondrial Integrity and Autophagy

“…FNDC5 signaling components play an important role in mediating the beneficial effects that physical activity and moderate exercise evoke, maintaining intracellular homeostasis and metabolism so as to stifle senescence programs, degeneration processes and inflammatory reactions in various tissues in aging, overweight and diabetic conditions [37]. The myokine also communicates via the muscle-bone axis pathway to regulate bone mineral acquisition and osteoporosis development [38], as well as orchestrating muscle-kidney interplay to control renal anabolism and nephropathy [39]. Of interest, regular moderate exercise is found to alleviate joint pain and severity of OA, improving the kinematic activity of injured knees and hips [1].…”

The Effect of Irisin as a Metabolic Regulator and Its Therapeutic Potential for Obesity

“…ese effects improve the WAT metabolic profile and enhance whole-body energy expenditure, making irisin a potential new therapeutic target for the treatment of obesity and its complications. More recent studies have shown that irisin also plays a potential role in bone metabolism [11,12], including improving osteoblastogenesis [13][14][15] and enhancing bone mass and bone mineral density (BMD) [16,17] in many physiological and pathological conditions. e relevance of irisin in humans has also been demonstrated [18][19][20].…”