Regional osteoporosis due to osteoclast activation as a trigger for the pain-like behaviors in tail-suspended mice

Abstract

Pathological conditions with refractory skeletal pain are often characterized by regional osteoporotic changes such as transient osteoporosis of the hip, regional migratory osteoporosis, or complex regional pain syndrome (CRPS). Our previous study demonstrated that the acidic microenvironment created by osteoclast activation under high bone turnover conditions induced pain-like behaviors in ovariectomized mice through the stimulation of acid-sensing nociceptors. The aim of the present study was to examine whether regional transient osteoporotic changes are related to pain-like behaviors in the hind limb using tail-suspended model mice. The hind limbs of tail-suspended mice were unloaded for 2 weeks, during which time the mice revealed significant regional osteoporotic changes in their hind limbs accompanied by osteoclast activation. In addition, these changes were significantly recovered by the resumption of weight bearing on the hind limbs for 4 weeks. Consistent with the pathological changes in the hind limbs, pain-like behaviors in the mice were induced by tail suspension and recovered by the resumption of weight bearing. Moreover, treatment with bisphosphonate significantly prevented the triggering of the regional osteoporosis and pain-like behaviors, and antagonists of the acid-sensing nociceptors, such as transient receptor potential channel vanilloid subfamily member 1 and acid-sensing ion channels, significantly improved the pain-like behaviors in the tail-suspended mice. We, therefore, believe that regional transient osteoporosis due to osteoclast activation might be a trigger for the pain-like behaviors in tail-suspended model mice. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1226-1236, 2017.

Effect of Zoledronic Acid and Denosumab in Patients With Low Back Pain and Modic Change: A Proof-of-Principle Trial

“…Elevated levels of osteoclast activators have been detected in intervertebral discs with adjacent MC compared to those without, meaning osteoclasts may be involved in the pathogenesis of MC. In animal experiments, osteoclastic bone resorption has been associated with inflammatory skeletal pain, which can be improved by the administration of bone‐active agents . Biomechanical theory suggests that traumatic inflammation in the endplates may be a source of MC‐associated LBP .…”

Update on the effects of microgravity on the musculoskeletal system

“…Numerous HLS studies have also shown a significant increase in osteoclast activity and number as well as a significant decrease in bone volume after 2–3 weeks of HLS 52 , 109 , 119 , 121 . The increased osteoclast activity results in an increased marrow cavity volume, decreased cortical thickness, increased trabecular porosity, and a weakening of bone mechanical properties 51 , 122 .…”

Pharmacology of bisphosphonates in pain

“…One of the most prominent hypotheses that has thus been put forward in many studies to explain the analgesic effects of bisphosphonates is that in situations of elevated bone turnover associated with increased osteoclast activity, higher levels of secreted protons result in increased acidification of the osteoclast environment. This would lead to an activation of acid‐sensing receptors such as TRPV1 channels and ASIC2/3, which are located on bone‐innervating primary afferents, as well as on bone tissue and b acid‐sensing ion channels (ASICs)one marrow cells (Dohke et al, 2017; Kanaya, Iba, Dohke, Okazaki, & Yamashita, 2016; Nagae et al, 2006; Nagae et al, 2007; Yoneda et al, 2011; Figure 1). The canonical inhibition of osteoclast activity by bisphosphonates would thus decrease extracellular acidification and consequently reduce ASIC‐ and TRPV1‐mediated activation of nociceptive primary afferents located in bone.…”

“…Many studies demonstrating analgesic effects of bisphosphonates in animal pain models have reported that osteoclast activity or number, or bone loss is concurrently reduced by bisphosphonate treatment. Of these studies, most did suggest a causal relationship between analgesia and effects on osteoclasts (Abe et al, 2015 [ovariectomy]; Dohke et al, 2017 [hindlimb‐unloading]; Sagar et al, 2014 [monoiodoacetate‐induced (MIA) OA model]; Sevcik et al, 2004 [bone cancer pain]; Hald et al, 2009 [bone cancer pain]; Moreau et al, 2011 [surgical OA model]; Strassle et al, 2010 [MIA OA model]; Yu et al, 2013 [MIA OA model]), but others concluded that such a relationship may not exist (Kim et al, 2013 [acetic acid writhing and capsaicin]; Wang et al, 2016 [CRPS]; Whiteside et al, 2006 [chronic constriction injury, spinal nerve ligation, and partial sciatic nerve ligation]; Suzuki et al, 2017 [ovariectomy]).…”