ABSTRACT:We have recently demonstrated that pathological changes leading to increased bone resorption by osteoclast activation are related to the induction of pain-like behavior in ovariectomized (OVX) mice. In addition, bisphosphonate and the antagonist of transient receptor potential vanilloid type 1 (TRPV1), an acid-sensing nociceptor, improved the threshold value of pain-like behaviors accompanying an improvement in the acidic environment in the bone tissue based on osteoclast inactivation. The aim of this study was to evaluate the effect of (i) an inhibitor of vacuolar H þ -ATPase, known as an proton pump, (ii) an antagonist of acid-sensing ion channel (ASIC) 3, as another acid-sensing nociceptor, and (iii) the P2X2/3 receptor, as an ATP-ligand nociceptor, on pain-like behavior in OVX mice. This inhibitor and antagonists were found to improve the threshold value of pain-like behavior in OVX mice. These results indicated that the skeletal pain accompanying osteoporosis is possibly associated with the acidic microenvironment and increased ATP level caused by osteoclast activation under a high bone turnover state. Skeletal pain resulting from fragility fractures and skeletal deformity is the most common problem observed in osteoporosis patients. 1 On the other hand, several studies have indicated that osteoporosis patients also experience idiopathic skeletal pain independent of those fractures or deformity. [2][3][4] One factor underlying the induction of idiopathic skeletal pain is the acidic microenvironment created by activated osteoclasts, which results in pain through the same mechanism as that observed for cancer-induced bone pain. 5,6 Moreover, recent studies have demonstrated that bisphosphonate (BP), an anti-bone resorption drug which works via the inhibition of osteoclast activity, improves skeletal pain in osteoporosis patients. 2,3,7 We have also demonstrated that the pathological changes leading to increased bone resorption by osteoclast activation are related to the induction of painlike behavior in an ovariectomized (OVX) mouse model. In addition, BP treatment improved the threshold value of the pain-like behavior accompanied by an improvement in the acidic environment in the bone tissue through osteoclast inactivation. 8 Furthermore, the antagonist to transient receptor potential vanilloid type 1 (TRPV1), a member of a family of polymodal and nonselective cation channels that are predominantly expressed by sensory nerve fibers and sensitized by protons, 9 was also found to improve the threshold value. 8 Therefore, we speculate that the skeletal pain accompanying osteoporosis is associated with the acidic microenvironment resulting from osteoclast activation.On the other hand, with regard to the improvement in the pain threshold, the effect of TRPV1 was likely to be limited in comparison with that of BP. These results encouraged us to clarify the other mechanisms by which pathological changes under a high bone turnover state resulting from osteoclast activation might induce skeletal pain in oste...

Tetranectin is a plasminogen-binding protein that enhances plasminogen activation, which has been suggested to play a role in tissue remodeling. Recently, we showed that tetranectin has a role in the wound-healing process. In this study, we investigated whether tetranectin plays a role in fracture healing. The fracture-healing process was studied using a femoral osteotomy model in tetranectin-null mice, previously generated by the authors. Radiographic imaging, micro-computed tomography (μCT), and histological analysis were used to evaluate osteotomy healing. In wild-type mice, a callus was apparent from 7 days, and most samples showed marked callus formation and rebridging of the cortices at the osteotomy site at 21 days. In contrast, in the tetranectin-null mice there was no callus formation at 7 days and much less callus formation and no bridging of cortices were observed at 21 days. At 35 days, all osteotomy sites showed clear rebridging, and secondary bone formation was achieved in wild-type mice by 42 days. In contrast, no clear rebridging or secondary bone formation was observed at 42 days in the tetranectin-null mice. Analysis using μCT at 21 days after osteotomy revealed that the callus area in tetranectin-null mice was smaller than that in wild-type mice. Histological analysis also showed that soft tissue and callus formation were smaller in the tetranectin-null mice at the early stage of the healing process after drill-hole injury. These results suggested that tetranectin could have a role in the positive regulation at the early stage of the fracture-healing process, which was reflected in the delayed fracture healing in tetranectin-deficient mice.

Daily teriparatide injections enhance bone union more than weekly injections in complete AFF patients.

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.

No abstract