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

Corinne E Metzger,Susan A Bloomfield,Peter H Phan,S Anand Narayanan

doi:10.1038/s41526-020-00118-4

Corinne E Metzger, Susan A Bloomfield + Show 2 more

Open Access

https://doi.org/10.1038/s41526-020-00118-4

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Abstract

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, n = 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.

Highlights

Bone is a highly adaptive tissue that responds to alterations in the mechanical strain environment
The primary findings of this study are (1) hindlimb unloading (HU) results in site-specific alterations in bone turnover with increased bone resorption and decreased bone formation in vertebral and hindlimb bone, with an opposite response in the forelimb based on the loading/ unloading condition, (2) osteocyte inflammatory proteins (TNF-α, IL-17) were elevated in the HU hindlimbs, but lower versus controls in the HU forelimbs, indicating site-specific and loadingspecific adaptations in osteocyte inflammatory response in conjunction with altered bone resorption and formation, and (3) treatment with exogenous irisin prevented the increased osteocyte inflammatory response in the unloaded hindlimb while having minimal impact in the loaded forelimb
Young male rats had 9% lower total volumetric bone mineral density (vBMD) and 39% lower cancellous vBMD at the proximal tibia metaphysis compared to ambulatory controls

Summary

Introduction

Bone is a highly adaptive tissue that responds to alterations in the mechanical strain environment. In various animal models of disuse, like the hindlimb unloading (HU) model and actual spaceflight, similar disuse-induced reductions in bone occur, in cancellous compartments[4,5,6,7,8]. With dendritic processes extending out through the lacuna-canalicular spaces forming vast communication networks, osteocytes sense mechanical strains and signal to osteoblasts and osteoclasts to alter bone turnover. Mice with targeted ablation of osteocytes develop an aging-like skeletal phenotype with intracortical porosity and microfractures, but are resistant to unloading-induced bone loss; these observations highlight the pivotal role of osteocytes both in overall skeletal health as well as in orchestrating alterations to unloading[15]

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