Remission of hypersensitivity by simple weight load stimuli in a complex regional pain syndrome mouse model.

Painful sensitivity of the hand or foot are the most common and debilitating symptoms of complex regional pain syndrome (CRPS). Physical therapy is standard treatment for CRPS, but evidence supporting its efficacy is minimal and it can be essentially impossible for CRPS patients to actively exercise the painful limb. Using the well-characterized distal tibial fracture CRPS mouse model, we compared the therapeutic effects of several weeks of daily hindlimb loading versus rotarod walking exercise. The effects of loading and exercise were evaluated by weekly testing of hind-paw withdrawal thresholds to von Frey fibers and radiant heat, as well as measurements of paw and ankle edema. At 6 weeks after fracture, the mice were killed and the ipsilateral femur, spinal cord and L4/5 dorsal root ganglia, and hind-paw skin collected for PCR assays and paw skin Immunohistochemistry evaluation. Hindlimb loading reduced hind-paw von Frey allodynia and heat hyperalgesia and edema within a week and these effects persisted for at least a week after discontinuing treatment. These therapeutic effects of loading exceeded the beneficial effects observed with rotarod walking exercise in fracture mice. Levels of nerve growth factor and transient receptor potential vanilloid 1 (TRPV1) immunostaining in the hind-paw skin were increased at 6 weeks after fracture, and both loading and exercise treatment reduced increases. Collectively, these results suggest that loading may be an effective and possibly curative treatment in CRPS patients with sensitivity in the affected limb.

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.

Surgical Procedures Based on the Arthrographic Findings of the Fifth MTP Joint With Proximal Phalanx Duplication in Postaxial Polydactyly of the Foot.

Radiographic findings in several atypical cases of postaxial polydactyly of the foot do not provide sufficient information to assess the cartilaginous structures or duplicated digit connections at the MTP joint. The purpose of this study was to demonstrate the surgical procedures using arthrography for the cartilaginous structures of the MTP joint in postaxial polydactyly of the foot. We performed arthrography in 7 feet of 7 patients with postaxial polydactyly of the foot in which duplication of the proximal phalanx was observed at the fifth MTP joint on the basis of radiographic evaluation. The average age at surgery was 13.5 months and average duration of postsurgical follow-up was 36 months. Individual surgical procedures were confirmed or modified during the operation by reference to the arthrographic findings. Radiographic and arthrographic findings were assessed in relation to the findings from direct observation of the cartilaginous structures at surgery. Postoperative malalignment, functional disturbance and pain in the reconstructed toe were evaluated. The arthrographic findings provided different forms of cartilaginous structures that could be categorized in 4 types, and reflected the cartilaginous connection visualized at surgery that could not be detected on radiographs in each case. No cases revealed any deformities, functional disturbance, or pain in the reconstructed toe after surgery. The parents' evaluation in each case was "very satisfied" or "satisfied." The arthrographic findings provided additional information regarding variations in the cartilaginous structures of the fifth MTP joint and for determining individual surgical procedure for postaxial polydactyly of the foot.

Long-term outcomes after corrective cartilaginous joint resection based on arthrographic findings of duplicated thumbs.

We report greater than 10-year outcomes in duplicated thumbs following corrective cartilaginous resection during the growth period. We have undertaken corrective resection of cartilaginous joint connections based on intraoperative arthrographic findings to reconstruct favourable alignment in six Wassel Type II and IV thumb duplication in six patients. The age at surgery was 13 months (range 10-15), and the average post-surgical follow-up was 134 months (range 120-160). We observed five excellent and one good outcome using the Japanese Society for Surgery of the Hand scoring method. Favourable joint congruency and alignment were preserved, and no growth plate arrest or joint space narrowing was present more than 10 years after surgery. We conclude that corrective resection of the cartilaginous joint based on intraoperative arthrographic findings has long-term reliability for duplicated thumbs, especially those of Wassel Type II and IV, which have a cartilaginous joint connection.Levels of evidence: IV.

Long-term outcomes after phalangeal distraction lengthening in patients with constriction band syndrome.

We investigated the long-term post-operative outcomes, more than 10 years after surgery, of distraction lengthening of phalanges in patients with congenital constriction band syndrome. Five shortened digits of two patients with congenital constriction band syndrome underwent distraction lengthening of the proximal phalanges using external fixator for the reconstruction of grasp and pinch at age of 53 and 41 months. The post-operative followed-up was 126 and 124 months. Subjective evaluation of hand function was performed using the tape measure method and Functional Dexterity Test pre-operatively and at 1 year after surgery. The parameters for proximal phalangeal distraction and the changes in the length ratio of the phalanges were evaluated. Grasp and pinch function was markedly improved after phalangeal lengthening. Regarding the radiographic findings, the length of distraction was 9.7 mm, % increase of lengthening: 52%, duration of distraction: 28 days, duration of fixation: 83 days, and healing index: 90 days. At the latest follow-up, the relative length of the proximal phalanx did not change significantly (-6%) during the 10 years after distraction lengthening. Patients with constriction band syndrome obtained favorable hand function and preserved those functions for more than 10 years after distraction lengthening of short phalanges using an external fixator.

Soft tissue injury in the limbs increased regional bone turnover.

BACKGROUND: Pathological conditions after skeletal tissue injury such as trauma and surgical intervention are often accompanied with regional osteoporotic changes, which are recognized to be mainly caused by limb immobility after injury. However, the mechanisms for the progression of regional osteoporotic changes related to the injury remains unknown. Previous studies reported that the pathophysiological conditions related to tissue injury include the acidic micro-environment formation and increased ATP levels. In addition, we previously demonstrated that those changes in the micro-environment induced a high bone turnover state through the activation of TRPV1, ASICs and P2X expressed in bone cells. We, therefore, hypothesized that tissue injury could enhance a high bone turnover state due to those pathophysiological changes in soft tissue in the injured limb. The aim of this study was to examine whether soft tissue injury associated with cutaneous incisions in a limb affects regional bone turnover. METHODS: Eight-week-old male C57BL/6 J mice underwent soft tissue injury associated with cutaneous incisions in the right femoral skin. During the 14 days after the incision, changes in the expression of osteoblast and osteoclast differentiation regulators and ATP were evaluated in comparison with those in uninjured mice. The pain-like behaviors and the expression of those differentiation regulators with and without treatment with bisphosphonate and Cox2 inhibitor were assessed in the injured limb. RESULTS: Consistent with the wound healing process, the expression levels of Osterix, osteocalcin and RANKL in the femur of the incised limb were significantly increased up to 7 days, and then decreased to the same level as those in the control limbs by 14 days after the incisions. The levels of TRAP 5b and ATP were initially significantly increased, and then decreased to the same level as before injury by day 14. Bisphosphonate significantly improved the pain-like behaviors in the injured limb associated with the inhibition of osteoblast and osteoclast differentiation regulators. CONCLUSION: We believe that the pathophysiological changes in soft tissue resulting from cutaneous incisions could be related to the induction of osteoblast and osteoclast differentiation regulators.

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.

Midterm and Long-term Follow-up After Surgical Reconstruction for Lateral Polydactyly of the Foot With Mosaic-like Alignment of the Phalanx Bones.

BACKGROUND: The phalanx bones in several cases of lateral polydactyly of foot revealed complicated alignment with radiographic findings revealing medial-protrusion and lateral deviation of the middle phalanx. We previously defined such cases as showing "mosaic-like alignment" and demonstrated favorable postoperative outcomes using our surgical procedure. The aim of this study was to evaluate the midterm and long-term postoperative outcomes in such cases. METHODS: The study included 17 feet from 16 patients; 5 male and 11 female, with one bilateral case. The radiographic findings in all cases revealed a mosaic-like alignment of phalanges. Average age of the patients at the initial surgery was 12 months and average duration of post-operative follow-up was 89 months (60 to 132 mo). The surgical procedures were focused on the alignment between the distal and proximal phalanges independent of the middle phalanx alignment. Ligamentous joint stability was restored using collateral ligament reconstruction. We retrospectively evaluated post-operative outcomes, and subjective evaluation by the patients and parents was carried out. RESULTS: No cases revealed either varus or valgus deformities, pigmentation of the grafted skin, or functional disturbance. As for postoperative complications, we observed visible thickening in 7 toes, 3 of which further underwent partial resection of the middle phalanx. Subjective evaluation of the postoperative results by the patients and parents was "very satisfied" or "satisfied" in 15 of 16 cases. CONCLUSION: On the basis of our midterm to long-term postoperative outcomes, we believe that our method of surgical reconstruction provides a new option for the treatment of lateral polydactyly of the foot with mosaic-like alignment of the phalanx bones. LEVEL OF EVIDENCE: Level IV-therapeutic studies.

Antagonists to TRPV1, ASICs and P2X have a potential role to prevent the triggering of regional bone metabolic disorder and pain-like behavior in tail-suspended mice.

Our recent studies demonstrated that regional bone loss in the unloaded hind limbs of tail-suspended mice triggered pain-like behaviors due to the acidic environment in the bone induced by osteoclast activation. The aims of the present study were to examine whether TRPV1, ASIC and P2X (known as nociceptors) are expressed in bone, and whether the antagonists to those receptors affect the expression of osteoblast and osteoclast regulators, and prevent the triggering of not only pain-like behaviors but also high bone turnover conditions in tail-suspension model mice. The hind limb-unloaded mice were subjected to tail suspension with the hind limbs elevated for 14days. The effects of the TRPV1, ASIC3, P2X2/3 antagonists on pain-like behaviors as assessed by the von Frey test, paw flick test and spontaneous pain scale; the expressions of TRPV1, ASICs, and P2X2 in the bone; and the effects of those antagonists on osteoblast and osteoclast regulators were examined. In addition, we evaluated the preventive effect of continuous treatment with a TRPV1 antagonist on the trigger for pain-like behavior and bone loss in tail-suspended mice. Pain-like behaviors were significantly improved by the treatment with TRPV1, ASIC, P2X antagonists; TRPV1, ASICs and P2X were expressed in the bone tissues; and the antagonists to these receptors down-regulated the expression of osteoblast and osteoclast regulators in tail-suspended mice. In addition, continuous treatment with a TRPV1 antagonist during tail-suspension prevented the induction of pain-like behaviors and regional bone loss in the unloaded hind limbs. We, therefore, believe that those receptor antagonists have a potential role in preventing the triggering of skeletal pain with associated regional bone metabolic disorder.

Sagittal band reconstruction in the index finger using a modified Elson technique.

PURPOSE: The Elson technique is a rigid reconstruction method for a hypoplastic or absent sagittal band in the treatment of chronic extensor digitorum communis (EDC) tendon dislocation. We performed a modified procedure based on the Elson technique for reconstruction of the radial sagittal band in case involving the index finger. We investigated the postoperative outcomes of chronic EDC dislocation after treatment with the original and modified Elson technique. METHODS: We examined five fingers of five patients (2 males and 3 females) with a mean age of 41 years. The chronic EDC tendon dislocation was due to an old trauma, or a spontaneous or congenital condition involving the index in two, middle in two, and ring finger in one patient. Sagittal band reconstruction was performed using the modified Elson technique for the index finger and the original technique for the other fingers. The mean duration of postoperative follow-up was 58 months. Clinical findings such as pain and discomfort at metacarpophalangeal flexion associated with the tendon dislocation, range of motion (ROM), and disabilities of the arm, shoulder and hand were evaluated. We also examined postoperative recurrence and subjective patient evaluation. RESULTS: All cases achieved pain-free stability of the EDC tendon with no recurrence, and full ROM was maintained at the latest examination after surgery. The postoperative subjective evaluation by the patients was "very satisfied" in four fingers and "neutral" in one finger. CONCLUSION: We demonstrated our modified Elson technique for the treatment of chronic extensor tendon dislocation of the index finger.

Treatment of forearm deformity with radial head dislocation because of multiple osteochondromas: a series of three cases treated by simple axis correction and distraction osteogenesis of the ulna.

Radial head dislocation in multiple osteochondroma leads to functional impairment and cosmetic problems, and surgical intervention has not been successful to date, with high rates of redislocation. Simple correction of the longitudinal axis and distraction oste8ogenesis of the ulna without corrective osteotomy of the radius were performed within 1 year of radial head dislocation. The mean age of the patients was 7.2 years and the postoperative follow-up duration was 63.6 months. In all cases, the dislocated radial head was repositioned without surgical invention involving the radius. All patients were pain free, with no impairment of daily activity, and all were satisfied with the cosmetic appearance, indicating successful medium-term postoperative outcomes for our surgical procedure.

Improvement in the rate of inadequate pharmaceutical treatment by orthopaedic surgeons for the prevention of a second fracture over the last 10 years.

BACKGROUND: We have previously reported that the low rate of osteoporosis patients treated with anti-osteoporotic drugs following surgical treatment for the first fragility fractures by orthopaedic surgeons during 3 years from 2000 to 2003 was only 13.1%. Ten years have now passed our previous study, and we hypothesized that the rate of appropriate pharmacologic treatment for the prevention of secondary fractures has improved. METHODS: We studied 730 osteoporosis patients (102 men and 628 women; average age of 78 years, range 33-102 years) who underwent surgical treatment for fragility fractures, during 3-year period from 2010 to 2012. The 730 cases consisted of 489 hip fractures and 241 distal radius fractures. All patients were admitted and underwent surgical intervention in hospitals. Variables were examined to ascertain whether pharmaceutical treatment was performed after discharge. Based on these data, we compared results for patients in the present study with those from our previous study. RESULTS: The rate of treatment with anti-osteoporosis medication in the present (16.2%) was slightly but significantly improved from that in our previous study (13.1%). The rate of pharmaceutical treatment following hip fractures increased significantly, while that following distal radius fractures showed no significant change. Regarding the categories of anti-osteoporotic drugs prescribed to the patients, the rate of treatment with bisphosphonate as a higher evidenced drug for the prevention of fractures in the present study was significantly higher than that in our previous study. CONCLUSION: We demonstrated that the rate of pharmacologic treatment by orthopaedic surgeons and the rate of more effective anti-osteoporotic drugs prescribed to the patients following surgical intervention for the first fragility fracture in the present study were improved in comparison with those of 10 years ago.

Teriparatide rapidly improves pain-like behavior in ovariectomized mice in association with the downregulation of inflammatory cytokine expression.

Recent studies have indicated that teriparatide, an anti-osteoporosis agent, significantly improves back pain regardless of the presence of vertebral fracture in osteoporosis patients. The aims of this study were to examine whether teriparatide improves pain-like behavior in an ovariectomized (OVX) mouse model, and to evaluate changes in osteoclast marker levels and inflammatory cytokine expression levels induced by teriparatide treatment in bone tissue in association with improvements in pain-like behavior. OVX and sham operations were performed in 8-week-old mice, followed by teriparatide treatment for 2 weeks. Pain-like behavior tests (von Frey, paw flick and spontaneous pain test), and the measurement of serum tartrate-resistant acid phosphatase 5b (TRAP5b) level and inflammatory cytokine (interleukin [IL]-1ß, IL-6 and tumor necrosis factor [TNF]-α) expression levels in the bone tissue were conducted after teriparatide treatment in OVX mice. Pain-like behavior in the von Frey test was significantly improved by teriparatide treatment in OVX mice. With regard to the early phase (within the first 7 days of treatment), teriparatide significantly improved pain-like behavior in the von Frey test, the paw flick test and the spontaneous pain test. Teriparatide significantly inhibited the expression of IL-1ß, IL-6 and TNF-α in OVX mice in the early phase of the treatment, while the TRAP5b level in OVX mice was not significantly affected. We demonstrated that the teriparatide-induced rapid improvement effect on pain-like behavior in OVX mice was associated with the downregulation of inflammatory cytokine expression, including IL-1ß, IL-6 and TNF-α.

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

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.