Static stretching of the ankle prevents cold hypersensitivity associated with limb immobilization in model mice.

BACKGROUND: Limb immobilization is considered to contribute to limb pain including hyperalgesia. Approximately 50% of patients with such chronic limb pain complain that their abnormal pain worsens after exposure to cold. However, there have been few studies on the relationship between limb immobilization and cold hypersensitivity. The aim of this study was to examine whether limb immobilization induces cold hypersensitivity, and whether physical exercise such as ankle stretching prevents its induction in model mice. METHOD: We used forty-four 8-week-old male C57Bl/6J mice, consisting of 32 immobilized mice and 12 control mice. The bilateral hind limbs of the mice were immobilized by a thermoplastic cast. After limb-immobilization for 1 week, changes in mechanical, thermal and cold hypersensitivity, and the expression levels of TRPV1, TRPA1, TRPM8, IL-1ß, IL-6, and TNFα in the spinal cord, dorsal root ganglia and the affected hind paw were evaluated in comparison with those in the control mice. In addition, we examined the effect of ankle stretching on the hypersensitivity and expression levels in the limb-immobilized mice. RESULTS: Mechanical, thermal and cold hypersensitivity were significantly increased in the limb-immobilized mice. In addition, ankle stretching during the immobilization period significantly prevented the increases in those hypersensitivities. There were no significant differences in the expression levels of TRPV1, TRPA1 and TRPM8 among the control, and limb-immobilized mice with and without ankle stretching. The expression levels of IL-1 and IL-6 were significantly increased in the immobilized hind limb paw. Furthermore, ankle stretching significantly prevented the increases in their expression levels. CONCLUSION: Limb-immobilization induced cold hypersensitivity as well as mechanical and thermal hypersensitivity, and ankle stretching significantly prevented the hypersensitivity induction in the model mice. It would be of great interest to clarify whether a patient with limb-immobilization experiences cold hypersensitivity and whether ankle stretching might prevent hypersensitivity induction in the future.

Delayed tendon healing after injury in tetranectin-deficient mice.

BACKGROUND: Tetranectin, a plasminogen-binding protein, is present in human serum and has a role in tissue remodeling. The wound healing process is established and follows a similar cascade in tendon tissue as in other tissues. In this study, we investigated whether tetranectin has a role in regulating tissue formation of injured tendon. METHODS: Using the patella tendon injury model in the tetranectin-null mice, healing processes of the injured tendon were evaluated by histological and immunohistochemical analyses, and measurement of the expression of tetranectin, type 1 collagen (Col 1), tenomodulin, scleraxis, TGFß, IL-1ß, IL-6 and TNF-α. RESULTS: At the inflammatory phase within 7 days after the injury, involvement of inflammatory cells and the expressions of IL-1ß, IL-6 and TNF-α were significantly decreased in tetranectin-null mice. Tetranectin expression increased at 1 day and peaked at 3 days, and finally disappeared at 7 days after the injury in wild-type mice. The tendon healing period and maturity were significantly delayed in the tetranectin-null mice. Expression levels of type 1 collagen and tenomodulin in tetranectin-null mice were significantly lower than those in the wild-type mice until 70 days after injury. With regard to the long-term processes, the healing and maturation of the injured tendon in tetranectin-null mice were eventually completed. CONCLUSION: We believe that tetranectin might have a potential role in enhancing tissue formation of healing tendon at the inflammatory phase after injuries. The characteristics of tetranectin as a purified protein from human serum could be interested in an attractive candidate as a potential agent to enhance tendon healing after injury.

High bone turnover state under osteoporotic changes induces pain-like behaviors in mild osteoarthritis model mice.

INTRODUCTION: Our previous studies demonstrated that a high bone turnover state under osteoporotic changes decreased the threshold of skeletal pain. Recent studies reported that the incidence of joint pain due to osteoarthritis (OA) in postmenopausal women was higher than that in males even with the same radiographic OA grade. The aim of this study was to evaluate whether a high bone turnover state affects the induction of pain-like behaviors in mild OA model mice. MATERIALS AND METHODS: We established mild OA model mice with accompanying osteoporotic changes by monosodium iodoacetate injection after ovariectomy. We assessed pain-like behaviors by von Frey test and paw-flick test; histological changes in OA joints; the expression of Runx2, Osterix, Osteocalcin, and Rankl; bone micro-architecture by µCT and measured serum tartrate-resistant acid-phosphatase 5b levels in the model mice. RESULTS: Pain-like behaviors in mice with OA and osteoporotic changes were significantly increased in comparison with those in OA mice without osteoporotic changes. The severity of histological OA changes did not differ significantly between the OA mice with and without osteoporotic changes. Bisphosphonate significantly improved pain-like behaviors accompanied with improvement in the high bone turnover state in the OA mice with osteoporosis, while it had no significant effect on pain-like behaviors in the OA mice without osteoporosis. In addition, the improvement was maintained for more than 4 weeks even after the discontinuation of bisphosphonate treatment. CONCLUSION: These results indicated that a high bone turnover state under osteoporotic changes could affect the induction of pain-like behaviors in mild OA model mice.

Hypersensitivity to cold stimulation associated with regional osteoporotic changes in tail-suspended mice.

INTRODUCTION: Cold intolerance is defined as abnormal pain resulting from exposure to cold stimulation after trauma. However, the pathophysiology remains unclear. We recently demonstrated that regional osteoporotic changes accompanied by high bone turnover were involved in causing pain-like behaviors in the unloaded hind limbs of tail-suspended mice. Bisphosphonate prevented pain-like behaviors and high bone turnover conditions in tail-suspended mice. The aims of this study were to examine the relationship between regional osteoporotic changes and the induction of hypersensitivity to cold stimulation. MATERIALS AND METHODS: The hind limbs of tail-suspended mice were unloaded for 2 weeks. The von Frey test and paw-flick test assessed pain-like behaviors and cold plate test evaluated cold escape behaviors. Furthermore, we examined whether cold hypersensitivity associated with regional osteoporotic changes could be improved by bisphosphonate, TRPV1 and TRPA1 antagonists. RESULTS: Hypersensitivity to cold stimulation was induced more noticeably in the tail-suspended mice, and this effect was related to the increased expression of bone metabolism markers. In addition, the cold hypersensitivity was improved by the resumption of weight bearing and prevented by bisphosphonate or a TRPV1 antagonist, and was accompanied with a decrease in the expression of bone metabolism markers. TRPA1 antagonist significantly improved the cold escape behavior, but had no significant effects on the expression of those markers. CONCLUSION: We demonstrated that the regional osteoporotic changes accompanying a high bone turnover state could be involved in the induction of hypersensitivity to cold stimulation in the tail-suspended mice.