Abstract
Interleukin-6 (IL-6) is widely accepted to stimulate osteoclasts. Our aim in this study was to examine whether the inhibitory effect of IL-6 on bone loss and skeletal pain associated with osteoporosis in hindlimb-unloaded (HU) mice in comparison with bisphosphonate. Eight-week-old male ddY mice were tail suspended for 2 weeks. Starting immediately after reload, vehicle (HU group), alendronate (HU-ALN group), or anti-IL-6 receptor antibody (HU-IL-6i group) was injected subcutaneously. After a 2-week treatment, pain-related behavior was examined using von Frey filaments. The bilateral distal femoral and proximal tibial metaphyses were analyzed three-dimensionally with micro-computed tomography. Calcitonin gene-related peptide (CGRP) expressions in dorsal root ganglion (DRG) neurons innervating the hindlimbs were examined using immunohistochemistry. HU mice with tail suspension developed bone loss. The HU mice showed mechanical hyperalgesia in the hindlimbs and increased CGRP immunoreactive neurons in the L3-5 DRG. Treatment with IL-6i and ALN prevented HU-induced mechanical hyperalgesia and upregulation of CGRP expressions in DRG neurons. Furthermore, ALN but not IL-6i prevented HU-induced bone loss. In summary, treatment with IL-6i prevented mechanical hyperalgesia in hindlimbs and suppressed CGRP expressions in DRG neurons of osteoporotic models. The novelty of this research suggests that IL-6 is one of the causes of immobility-induced osteoporotic pain regardless improvement of bone loss.
Highlights
The loss of muscle tension and gravity in the bones, especially in the trunk and extremity bones, during immobilization leads to loss of calcium from the bones, leading to osteoporosis [1]
We aimed to investigate pain-related behavior and bone structure to elucidate the mechanism of osteoporotic pain in hindlimb-unloaded (HU) mice treated with IL-6 receptor inhibitor (IL-6i) in comparison
The mice were tail suspended for 2 weeks, and all mice were reloaded after a 2-week tail suspension
Summary
The loss of muscle tension and gravity in the bones, especially in the trunk and extremity bones, during immobilization leads to loss of calcium from the bones, leading to osteoporosis [1]. Osteoporosis progresses over time and may show little or no apparent sign of progression until pathological fracture of the bone occurs [2]. Hindlimb suspension of rodents by the tail is a well-established approach for creating ground-based models for microgravity and musculoskeletal disuse that mimic many of the physiological changes associated with space flight as well as bed rest [3,4]. Hindlimb unloading by tail suspension demonstrated marked bone loss, osteoclast numerical increase, and mechanical hyperalgesia in the hindlimbs, which are prevented by bisphosphonate (BP) treatment. BP treatment prevents upregulation of the neuropeptide pain marker CGRP (calcitonin gene-related peptide) and acid-sensing receptor TRPV1
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