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

Disuse-induced bone loss is characterized by alterations in bone turnover. Accruing evidence suggests that osteocytes respond to inflammation and express and/or release pro-inflammatory cytokines; however, it remains largely unknown whether osteocyte inflammatory proteins are influenced by disuse. The goals of this project were (1) to assess osteocyte pro-inflammatory cytokines in the unloaded hindlimb and loaded forelimb of hindlimb unloaded rats, (2) to examine the impact of exogenous irisin during hindlimb unloading (HU). Male Sprague Dawley rats (8 weeks old,  = 6/group) were divided into ambulatory control, HU, and HU with irisin (HU + Ir, 3×/week). Lower cancellous bone volume, higher osteoclast surfaces (OcS), and lower bone formation rate (BFR) were present at the hindlimb and 4th lumbar vertebrae in the HU group while the proximal humerus of HU rats exhibited no differences in bone volume, but higher BFR and lower OcS vs. Con. Osteocyte tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17), RANKL, and sclerostin were elevated in the cancellous bone of the distal femur of HU rats vs. Con, but lower at the proximal humerus in HU rats vs. Con. Exogenous irisin treatment increased BFR, and lowered OcS and osteocyte TNF-α, IL-17, RANKL, and sclerostin in the unloaded hindlimb of HU + Ir rats while having minimal changes in the humerus. In conclusion, there are site-specific and loading-specific alterations in osteocyte pro-inflammatory cytokines and bone turnover with the HU model of disuse bone loss, indicating a potential mechanosensory impact of osteocyte TNF-α and IL-17. Additionally, exogenous irisin significantly reduced the pro-inflammatory status of the unloaded hindlimb.