DSS-induced colitis produces inflammation-induced bone loss while irisin treatment mitigates the inflammatory state in both gut and bone

Abstract

Chronic pediatric inflammatory bowel disease (IBD) leads to lack of bone accrual, bone loss, and increased fractures. Presently there is no cure, and many IBD treatments incur negative side effects. We previously discovered treatment with exogenous irisin resolved inflammatory changes in the colon, gut lymphatics, and bone in a mild IBD rodent model. Here we assess irisin treatment in severe IBD induced via dextran sodium sulfate (DSS). Male Sprague Dawley rats (2-mo-old) were untreated (Con) or given 2% DSS in drinking water. In week two, half of each group (Con + Ir and DSS + Ir) received injections of recombinant irisin (i.p., 2x/wk). After 4 weeks, gut inflammation was associated with declines in bone mineral density and cancellous bone volume. Furthermore, elevated osteocyte TNF-α, interleukin-6, RANKL, OPG, and sclerostin corresponded with higher osteoclast surfaces and lower bone formation rate in DSS animals as well as lower ultimate load. While irisin treatment improved colon inflammation, there were no improvements in bone density or bone mechanical properties; however, irisin elevated bone formation rate, decreased osteoclast surfaces, and reduced osteocyte pro-inflammatory factors. These data highlight the negative impact of chronic gut inflammation on bone as well as the therapeutic potential of irisin as an anti-inflammatory treatment.

Hindlimb unloading causes regional loading-dependent changes in osteocyte inflammatory cytokines that are modulated by exogenous irisin treatment

“…Pro-inflammatory cytokines TNF-α and IL-17 are both potent stimulators of osteoclasts and synergize with RANKL to increase osteoclastogenesis 22,24,56,57 . Previously, we identified increased osteocyte pro-inflammatory cytokines in age-matched ambulatory rats with systemic inflammation 51,52 . In this study, we aimed to determine if these factors were altered in HU.…”

“…We, therefore, do not know the time course of changes in osteocyte proteins over the period of disuse nor the impact of irisin treatment at various timepoints. Additionally, we only utilized one dose of irisin that we previously determined mitigated inflammatory responses in chronic models of IBD model 51,52 . We also did not incorporate ambulatory irisin only controls, but based on our previous work (utilizing animals of the same age, sex, strain, and diet), we did not find significant differences in irisin treatment in the ambulatory controls 51,52 .…”

“…At 7 weeks of age, rodents were switched from the standard rodent chow of the animal facility (Teklad 2018; Envigo, Houston, TX, USA) to the purified AIN93G chow for growing rodents (Research Diets, Inc., New Brunswick, NJ, USA). The age of animals and the diet were utilized to compare to previous work with age-matched and diet-matched groups 51,52 . At 8 weeks of age, animals were randomly divided into three different groups (n = 6/group): ambulatory cage control (Con), hindlimb unloaded (HU), and hindlimb unloaded with exogenous irisin treatment (HU + Ir).…”

“…One myokine is irisin, originally described as a metabolic regulator stimulating the browning of adipose 45 . Recent research has explored how irisin also increases osteoblasts and cortical bone mass [46][47][48] and regulates inflammation [49][50][51][52][53] . Previously, we discovered that exogenous irisin treatment ameliorated the inflammatory response of gut and bone in a rodent model of chronic IBD 51,52 .…”

“…Recent research has explored how irisin also increases osteoblasts and cortical bone mass [46][47][48] and regulates inflammation [49][50][51][52][53] . Previously, we discovered that exogenous irisin treatment ameliorated the inflammatory response of gut and bone in a rodent model of chronic IBD 51,52 . Another study found that administration of irisin prevented disuse-induced bone loss in HU 54 , but whether this was due to alterations of inflammatory factors has not been previously addressed.…”