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Background Musculoskeletal disorders are a key cause of morbidity in elderly people. How musculoskeletal disorders relate to healthy life expectancy remain elusive. Hence, we aimed to estimate gains in healthy life expectancy from the elimination of musculoskeletal diseases and injuries by using recent national health statistics data in Japan. Methods Mortality data were taken from Japanese national life tables and death certificates in 2016. Information on medical diagnoses, injuries, and activity were obtained from the 2016 Comprehensive Survey of Living Conditions. We examined five disorders: rheumatoid arthritis, arthrosis, low back pain, osteoporosis, and fracture. The prevalence of limitations in activities of daily living (ADL) in the population after eliminating the disorder was estimated as the proportion of outpatients without the disorder and ADL limitations, inpatients without the disorder in hospitals and clinics, and people without the disorder who reside in long-term elderly care facilities. Results There were small gains in life expectancy from elimination of all selected musculoskeletal disorders (0.0–0.1 years). Elimination of rheumatoid arthritis, osteoporosis, and fracture slightly increased the expected years without activity limitation (0.1–0.4) and slightly decreased years with activity limitation (0.1–0.4 years). Meanwhile, elimination of arthrosis, low back pain, and arthrosis and low back pain moderately increased expected years without activity limitation (0.3–1.5 years) and decreased years with activity limitation (0.3–1.5 years). In addition, elimination of rheumatoid arthritis, arthrosis, low back pain, osteoporosis, and fracture decreased expected years with ADL limitations (0.0–0.8 years) and non-ADL limitations (0.0–0.3 years). A combination of arthrosis and low back pain showed a moderate decrease in expected years with both ADL limitations (0.7–1.1 years) and non-ADL limitations (0.3–0.4). Conclusions These findings provide clinical evidence that among the musculoskeletal disorders low back pain and arthrosis are the key factors for the elongation of healthy life expectancy.

Background Idiopathic osteonecrosis of the femoral head (ONFH) frequently occurs after liver transplantation (LT) because of lifelong administration of corticosteroids or immunosuppressants and often requires total hip arthroplasty (THA). This study examines patient characteristics and short-term outcomes of THA after LT. Methods We observed 9 hips in 7 patients who underwent THA from August 2015 to December 2017 for ONFH after LT (group L). Cementless implants were inserted in all hips. Medical records were retrospectively reviewed to reveal reasons for LT, type of donor, and period from LT to THA. Preoperative laboratory data, operative time, intraoperative blood loss, complication rates, and Harris Hip Score were compared with a control group of 27 cementless THAs in 27 patients with ONFH. Results Causative diseases were liver cirrhosis (n = 4), type B fulminant hepatitis (n = 1), congenital biliary atresia (n = 1), and iatrogenic biliary tract injury (n = 1). Four livers were from living donors and 3 from cadavers. Mean time from LT to THA was 10.4 (1-20) years. Preoperative blood test showed a significant decrease in platelet count (178 vs 268 [∗103/μl]) and rise in total bilirubin (1.1 vs 0.7 [mg/dL]) in group L. There was no significant difference in operative time (86 vs 100 [minutes]), but intraoperative blood loss (303 vs 163 [mL]) increased significantly in group L. There were no significant differences in complication incidence or Harris Hip Score between the 2 groups. Conclusion THA after LT requires caution because risks for bleeding increase. However, short-term outcomes appear to be equivalent to normal THA.

Purpose A close relationship between sagittal spinal alignment and hip osteoarthritis (OA) has been documented. This study aimed to examine the relationship between hip joint proximity area and sagittal balance parameters in healthy subjects. Methods This prospective study enrolled 47 healthy volunteers who underwent 320-detector row upright computed tomography. Acquired data were reconstructed in a virtual three-dimensional space. The proximity area was determined by t test. Results The anterior proximity group (n = 24) had higher SVA (p = 0.016) and T1-Spi (p = 0.015) than the posterior proximity group (n = 23). CAM-HA-offset was higher in the posterior than in the anterior proximity group (p p > 0.05). Conclusion The anterior proximity group had a positive anterior spinal balance; the posterior proximity group may have a more posterior gravity line than the hip joint centre. The anterior spinal balance may contribute to the anterior loading of the hip joint, with known relation with the initiation and onset of hip OA.

Vitamin D deficiency is a recognized risk factor for sarcopenia development, but mechanisms underlying this outcome are unclear. Here, we show that low vitamin D status worsens immobilization-induced muscle atrophy in mice. Mice globally lacking vitamin D receptor (VDR) exhibited more severe muscle atrophy following limb immobilization than controls. Moreover, immobilization-induced muscle atrophy was worse in neural crest-specific than in skeletal muscle-specific VDR-deficient mice. Tnfα expression was significantly higher in immobilized muscle of VDR-deficient relative to control mice, and was significantly elevated in neural crest-specific but not muscle-specific VDR-deficient mice. Furthermore, muscle atrophy induced by limb immobilization in low vitamin D mice was significantly inhibited in Tnfα-deficient mice. We conclude that vitamin D antagonizes immobilization-induced muscle atrophy via VDR expressed in neural crest-derived cells.

Skeletal muscle is known to regulate bone homeostasis through muscle-bone interaction, although factors that control this activity remain unclear. Here, we newly established Smad3-flox mice, and then generated skeletal muscle-specific Smad2/Smad3 double conditional knockout mice (DcKO) by crossing Smad3-flox with skeletal muscle-specific Ckmm Cre and Smad2-flox mice. We show that immobilization-induced gastrocnemius muscle atrophy occurring due to sciatic nerve denervation was partially but significantly inhibited in DcKO mice, suggesting that skeletal muscle cell-intrinsic Smad2/3 is required for immobilization-induced muscle atrophy. Also, tibial bone atrophy seen after sciatic nerve denervation was partially but significantly inhibited in DcKO mice. Bone formation rate in wild-type mouse tibia was significantly inhibited by immobilization, but inhibition was abrogated in DcKO mice. We propose that skeletal muscle regulates immobilization-induced bone atrophy via Smad2/3, and Smad2/3 represent potential therapeutic targets to prevent both immobilization-induced bone and muscle atrophy.

Pain is an undesirable sensory experience that can induce depression and limit individuals’ activities of daily living, in turn negatively impacting the labor force. Affected people frequently feel pain during activity; however, pain is subjective and difficult to judge objectively, particularly during activity. Here, we developed a system to objectively judge pain levels in walking subjects by recording their quantitative electroencephalography (qEEG) and analyzing data by machine learning. To do so, we enrolled 23 patients who had undergone total hip replacement for pain, and recorded their qEEG during a five-minute walk via a wearable device with a single electrode placed over the Fp1 region, based on the 10–20 Electrode Placement System, before and three months after surgery. We also assessed subject hip pain using a numerical rating scale. Brain wave amplitude differed significantly among subjects with different levels of hip pain at frequencies ranging from 1 to 35 Hz. qEEG data were also analyzed by a support vector machine using the Radial Basis Functional Kernel, a function used in machine learning. That approach showed that an individual’s hip pain during walking can be recognized and subdivided into pain quartiles with 79.6% recognition Accuracy. Overall, we have devised an objective and non-invasive tool to monitor an individual’s pain during walking.

Background The locomotive syndrome risk test was developed to quantify the decrease in mobility among adults, which could eventually lead to disability. The purpose of this study was to establish reference values for the locomotive syndrome risk test for adults and investigate the influence of age and sex. Methods We analyzed 8681 independent community dwellers (3607 men, 5074 women). Data pertaining to locomotive syndrome risk test (the two-step test, the stand-up test, and the 25-question geriatric locomotive function scale [GLFS-25]) scores were collected from seven administrative areas of Japan. Results The reference values of the three test scores were generated and all three test scores gradually decreased among young-to-middle-aged individuals and rapidly decreased in individuals aged over 60 years. The stand-up test score began decreasing significantly from the age of 30 years. The trajectories of decrease in the two-step test score with age was slightly different between men and women especially among the middle-aged individuals. The two physical test scores were more sensitive to aging than the self-reported test score. Conclusion The reference values generated in this study could be employed to determine whether an individual has mobility comparable to independent community dwellers of the same age and sex.

Background: Venous thromboembolism (VTE) remains a major complication after total hip arthroplasty (THA), irrespective of the surgical approach. This study investigated the incidence of VTE in patients undergoing THA through intermuscular minimally invasive surgical techniques, which included a direct anterior approach (DAA), an anterolateral approach (AL), and anterolateral supine approach (ALS), at a single institution. Methods: One hundred consecutive patients treated with each surgical approach were evaluated. Plasma D-dimer levels 1 month preoperatively and 1 day postoperatively, operative time, and intraoperative blood loss were recorded, and the presence of VTE was evaluated based on multidetector row computed tomography performed the day after surgery. Student’s t-test and Pearson’s chi-square test or one-way analysis of variance were used in statistical analysis. Results: No differences among the groups in terms of age, height, weight, operative time, intraoperative bleeding, and preoperative and postoperative D-dimer levels were observed. The overall incidence of VTE was 21%. The incidences of VTE were 30% in AL, 17% in ALS, and 16% in DAA, representing a significantly higher rate in AL than in ALS and DAA (P=0.025). The incidences of VTE on the operated side were 19% in AL, 13% in ALS, and 12% in DAA, with no statistically significant differences. The incidences of VTE on the non-operated side were 22% in AL, 9% in ALS, and 8% in DAA; these differences were statistically significant (P=0.0045). Conclusions: Results showed that the incidence of VTE was significantly higher in AL than in ALS and DAA, especially for the non-operated side.

Hyaluronan (HA)-binding protein involved in HA depolymerization (HYBID), also called cell migration-inducing protein (CEMIP; alias KIAA1199), plays a key role in the degradation of HA in skin and arthritic synovial fibroblasts, but its functions in osteoarthritic (OA) cartilage remain elusive. Here, we investigated the expression and roles of HYBID in human OA cartilage. HYBID was highly expressed by chondrocytes in the HA-depleted area of OA cartilage, and HYBID immunoreactivity was correlated with Mankin score, the histopathologic severity of OA lesions of cartilage. Real-time quantitative PCR indicated that HYBID expression was significantly higher in OA cartilage than in control cartilage. In addition, OA chondrocytes exhibited HA-degrading activity, which was abolished by knock-down of HYBID by siRNAs. Although OA chondrocytes also expressed certain levels of hyaluronidases 1 and 2 and CD44, knock-down of these molecules exhibited negligible effects on HA degradation. Double immunostaining of HYBID and clathrin heavy chain revealed that HYBID was localized in the clathrin-coated vesicles, and HA was endocytosed within the vesicles of OA chondrocytes. Among eight factors including cytokines and growth factors examined, only tumor necrosis factor α stimulated OA chondrocytes to overexpress HYBID. These data are the first to demonstrate that HYBID is up-regulated in OA cartilage, and suggest that tumor necrosis factor α-stimulated HYBID plays a role in HA degradation in OA cartilage.

Introduction: Herein, we describe and evaluate a curved periacetabular osteotomy (CPO) via an intermuscular approach (IM-CPO) between the sartorius and iliac muscles. Methods: Between January 2009 and January 2016, IM-CPO was performed in 17 joints (16 patients), and a traditional CPO was performed in 17 joints. The length of incision at wound closure, operative time, intraoperative blood loss, serum creatinine kinase (CK) level the day after surgery, correctional angle, walking ability assessed using the gait items of the Harris Hip Score (at 3 and 6 months after surgery), and perioperative complications were evaluated. Group differences were assessed using t-tests. Results: The IM-CPO and CPO groups did not differ in the mean operative time (130 minutes and 124 minutes, respectively), mean serum CK the day after surgery (349 IU/L and 425 IU/L, respectively), or mean correctional angle (24.9° and 24.6°, respectively). The mean incision length was significantly shorter in the IM-CPO group (8.3 cm) compared to that in the CPO group (9.5 cm). The mean walking ability was significantly higher in the IM-CPO group (24.2 points) compared to that in the CPO group (20.9 points) at 3 months after surgery, but not at 6 months after surgery (26.4 points and 24.9 points, respectively). No serious complications were observed in either group. Conclusion: In addition to demonstrating a similarly satisfactory correctional angle, IM-CPO is anticipated to enable early weight-bearing and recovery of walking ability. Thus, IM-CPO is considered a superior surgical technique.

Osteoclasts and foreign body giant cells (FBGCs) are derived from common progenitors and share properties such as multi-nucleation capacity induced by cell-cell fusion; however, mechanisms underlying lineage determination between these cells remain unclear. Here we show that, under inflammatory conditions, osteoclasts are stimulated in a manner similar to M1 macrophages, while formation of FBGCs, which exhibit M2-like phenotypes, is inhibited in a manner similar to that seen in M1/M2 macrophage polarization. FBGC/osteoclast polarization was inhibited by conditional knockout of tumor necrosis factor receptor associated factor 6 (Traf6) in adults in vivo and in vitro. Traf6-null mice were previously reported to die soon after birth, but we found that Traf6 deletion in adults did not cause lethality but rather inhibited osteoclast activation and prevented FBGC inhibition under inflammatory conditions. Accordingly, basal osteoclastogenesis was significantly inhibited by Traf6 deletion in vivo and in vitro and accompanied by increased bone mass. Lipopolysaccharide-induced osteoclast formation and osteolysis were significantly inhibited in Traf6 conditional knockout mice. Our results suggest that Traf6 plays a crucial role in regulating M1 osteoclast and M2 FBGC polarization and is a potential therapeutic target in blocking FBGC inhibition, antagonizing osteolysis in inflammatory conditions, and increasing bone mass without adverse effects in adults.

Skeletal muscle atrophy promotes muscle weakness, limiting activities of daily living. However, mechanisms underlying atrophy remain unclear. Here, we show that skeletal muscle immobilization elevates Smad2/3 protein but not mRNA levels in muscle, promoting atrophy. Furthermore, we demonstrate that myostatin, which negatively regulates muscle hypertrophy, is dispensable for denervation-induced muscle atrophy and Smad2/3 protein accumulation. Moreover, muscle-specific Smad2/3-deficient mice exhibited significant resistance to denervation-induced muscle atrophy. In addition, expression of the atrogenes Atrogin-1 and MuRF1, which underlie muscle atrophy, did not increase in muscles of Smad2/3-deficient mice following denervation. We also demonstrate that serum starvation promotes Smad2/3 protein accumulation in C2C12 myogenic cells, an in vitro muscle atrophy model, an effect inhibited by IGF1 treatment. In vivo, we observed IGF1 receptor deactivation in immobilized muscle, even in the presence of normal levels of circulating IGF1. Denervation-induced muscle atrophy was accompanied by reduced glucose intake and elevated levels of branched-chain amino acids, effects that were Smad2/3-dependent. Thus, muscle immobilization attenuates IGF1 signals at the receptor rather than the ligand level, leading to Smad2/3 protein accumulation, muscle atrophy, and accompanying metabolic changes.

The number of osteoporosis patients is increasing not only in women but in men. Male osteoporosis occurs due to aging or androgen depletion therapies, leading to fractures. However, molecular mechanisms underlying male osteoporosis remain unidentified. Here, we show that hypoxia inducible factor 1 alpha (Hif1α) is required for development of testosterone deficiency-induced male osteoporosis. We found that in mice Hif1α protein accumulates in osteoclasts following orchidectomy (ORX) in vivo. In vitro, Hif1α protein accumulated in osteoclasts cultured in hypoxic conditions, but Hif1α protein rather than mRNA levels were suppressed by testosterone treatment, even in hypoxia. Administration of a Hif1α inhibitor to ORX mice abrogated testosterone deficiency-induced osteoclast activation and bone loss but did not alter osteoclast activities or bone phenotypes in sham-operated, testosterone-sufficient animals. We conclude that Hif1α protein accumulation due to testosterone-deficiency promotes development of male osteoporosis. Thus Hif1α protein could be targeted to inhibit pathologically-activated osteoclasts under testosterone-deficient conditions to treat male osteoporosis patients.

Insulin-like growth factor-I (IGF-I) is a peptide with diverse functions, among them regulation of embryonic development and bone homeostasis. Serum IGF-I levels decline in the elderly; however, IGF-I function in adults has not been clearly defined. Here, we show that IGF-I is required to maintain muscle mass in adults. We crossed Igf-I flox’d and Mx1 Cre mice to yield Mx1 Cre/Igf-Iflox/flox (IGF-I cKO) mice, and deleted Igf-I in adult mice by polyIpolyC injection. We demonstrate that, although serum IGF-I levels significantly decreased after polyIpolyC injection relative to (Igf-Iflox/flox) controls, serum glucose levels were unchanged. However, muscle mass decreased significantly after IGF-I down-regulation, while bone mass remained the same. In IGF-I cKO muscle, expression of anabolic factors such as Eif4e and p70S6K significantly decreased, while expression of catabolic factors MuRF1 and Atrogin-1 was normal and down-regulated, respectively, suggesting that observed muscle mass reduction was due to perturbed muscle metabolism. Our data demonstrate a specific role for IGF-I in maintaining muscle homeostasis in adults.

Background Although a simple bone cyst carries the risk of pathological fractures, it rarely causes severe deformity. Here we report a case of severe femoral deformity after multiple pathological fractures due to simple bone cysts, and consider the reason for the progression of malunion despite multiple previous treatments. Finally, we propose a treatment option for malunion correction. Case presentation A 9-year, 7-month-old Japanese girl was referred to our facility with obvious deformity of her right femur, caused by multiple simple bone cyst-related pathological fractures. The deformity included bowing of approximately 90° and an internal rotation of 60° in the middle third of the femoral shaft. To correct this deformity, we excised the lesion, thus shortening the femur, then corrected the alignment and applied an Ilizarov fixator to extend the bone. At present, 3 years after surgery, the deformity has not recurred and our patient is living without any limitations in daily activities or regular exercise. Conclusions When a long bone is in a prolonged state of deformation, the deformity not only progresses as the bone grows, but the soft tissues remain unbalanced and treatment becomes increasingly difficult. To prevent increasing bone deformity and fragility, the deformity should be corrected as quickly as possible using intramedullary nailing or other fixation techniques. We believe that our shortening-distraction method is effective for the treatment of severe deformity with unbalanced soft tissues.

Prediction of pelvic displacement before total hip arthroplasty (THA) is important for accurate acetabular implant placement. This study aimed to evaluate the effect of contralateral joint conditions on pelvic displacement after THA.A total of 355 cases that underwent computed tomography before and after THA for osteoarthritis due to developmental dysplasia were assessed. The pelvic plane was based on preoperative and postoperative day 1 computed tomography images. The displacement in the anteversion direction was expressed as +. Subjects with a minimal joint space2 mm in the contralateral hip joint were in group N; subjects with ≥2 mm were in group W; subjects with THA were in group P; and subjects who underwent THA simultaneously on both sides were in group B. The Bartlett test was used when conducting the equal variance test among the groups. The F test was used for pairwise comparison. A P value.01 was considered statistically significant.Groups N, W, P, and B had 49, 227, 55, and 24 cases, respectively, and their displacements were -0.2° ± 2.7°, 0.8° ± 3.9°, 0.5° ± 2.6°, and 1.1° ± 4.0°, respectively; the variance between the groups was significantly different (P = .0001). The differences between groups W and N (P = .0020), between groups W and P (P = .0003), and between groups P and B (P = .0086) were statistically significant.When the contralateral joint space is wide, the variance of the displacement is high. The contralateral joint affects pelvic displacement.

Segmental bone transport (SBT) is a revolutionary method for treating extensive bone defects, and it is in wide clinical use. Although external fixation is generally used to perform SBT, it is associated with problems such as complications due to pin placement and limitations of the amount and rate of lengthening. As a way to overcome these problems we developed a novel intramedullary (IM) nail for SBT that minimizes damage to the surrounding tissue and improves the amount and rate of bone lengthening. The purpose of this study was to perform SBT in the femur of beagle dogs using the novel IM nail that we devised, and to evaluate the morphology and quality of the regenerated bone and circulation status in the surrounding tissue. We also considered the possibilities and limitations of the IM in regard to clinical application.This experiment was conducted on six beagle dogs. The novel IM nail we devised was inserted into the marrow cavity of the femur, and a 30-mm bone defect was created. After a 7-day postoperative waiting period, a bone segment was transported by 1.0 mm per day in two 0.5-mm increments. Because the nail broke in two dogs, they received only partial elongation by 15 mm over a 15-day period, with a 15-mm defect remaining, whereas full elongation by 30 mm in 30 days was performed in the other four dogs. The elongation was followed by a 30-day bone hardening period.The macroscopic and histological results demonstrated that high-quality, new bone had replaced the 30-mm bone defect created in the femur of all six dogs. The density and number of blood vessels that had penetrated the elongated segment of bone from the surrounding muscles was greater than in the corresponding segment of the contralateral femur, which served as a control. The results imply that the traction stimulus induced vigorous angiogenesis in the surrounding tissue.We concluded that this method has tremendous potential for clinical application, and will overcome the limitations of conventional external fixators.

Artificial joint acetabular cup stability is essential for successful total hip arthroplasty. However, a quantitative evaluation approach for clinical use is lacking. We developed a resonance frequency analysis (RFA) system involving a laser system that is fully contactless. This study aimed to investigate the usefulness of laser RFA for evaluating acetabular cup stability. First, the finite element method was performed to determine the vibration mode for analysis. Second, the acetabular cup was press-fitted into a reamed polyurethane cavity that replicated the human acetabular roof. The implanted acetabular cup was vibrated with pulse laser irradiation and the induced vibration was detected with a laser Doppler vibrometer. The time domain signal from the vibrometer was analyzed by fast Fourier transform to obtain the vibration frequency spectrum. After laser RFA, the pull-down force of the acetabular cup was measured as conventional implant fixation strength. The frequency of the first highest amplitude between 2 kHz and 6 kHz was considered as the resonance peak frequency, and its relationship with the pull-down force was assessed. The peak frequency could predict the pull-down force (R2 = 0.859, p &lt, 0.000). Our findings suggest that laser RFA might be useful to measure acetabular cup stability during surgery.

Aseptic loosening is the devastating long term complication of total hip arthroplasty and orthopedic implant debris has been shown to trigger an intense inflammatory reaction leading to resorption of the bone matrix. Inflammatory cytokines, such as tumor necrosis factor-α (TNFα), have been implicated in this process and osteocytes may play a role in its production. We previously demonstrated that cobalt-chromium-molybdenum (CoCrMo) particles upregulate TNFα production by MLO-Y4 osteocytes in vitro, but the underlying mechanism has not been elucidated. Based on previous studies by others, we hypothesized that the calcineurin-nuclear factor of activated T cells (NFAT) pathway mediates CoCrMo particle-induced TNFα production in MLO-Y4 osteocytes. MLO-Y4 osteocytes exposed to CoCrMo particle treatment resulted in a rapid and significant increase in calcineurin activity. We also demonstrate that CoCrMo particle-induced upregulation of TNFα is reduced to control levels with calcineurin-NFAT inhibitors and this was also confirmed at mRNA level. Moreover, we demonstrate the localization of NFATs in MLO-Y4 osteocytes and that NFAT1 and 2 translocate to the nucleus upon CoCrMo particle treatment. Our results suggest that calcineurin-NFAT signaling is involved in TNFα production by MLO-Y4 osteocytes after CoCrMo particle treatment.

Wear debris-induced osteolysis is purportedly the limiting problem affecting the long term results of joint arthroplasty. Pathogenic effects of wear debris in peri-implant cells such as macrophages, osteoblasts and osteoclasts have been well studied. In contrast, the effects of wear debris on osteocytes, which make up over 90% of all bone cells, remain unknown. We hypothesized that metal implant debris can induce the pro-inflammatory response in osteocytes. This study demonstrated the effects of cobalt-chromium-molybdenum alloy (Co-Cr-Mo) particles on a well-characterized MLO-Y4 osteocyte cell line. Co-Cr-Mo alloy particle treatment significantly (p0.05) up-regulated tumor necrosis factor alpha (TNFalpha) gene expression after 3 and 6 h and TNFalpha protein production after 24 h, but down-regulated interleukin-6 (IL-6) gene expression after 6 h. Co-Cr-Mo alloy particle treatment also induced osteocyte apoptosis after 24 h. This apoptotic effect was partially (40%) dependent on TNFalpha. Therefore, our results suggest that osteocytes play a role in particle-induced inflammation and bone resorption following total joint arthroplasty by inducing pro-inflammatory cytokines and inducing osteocyte apoptosis.

Background Preserving the hip joint to delay arthroplasty for patients with acetabular dysplasia-associated early-stage osteoarthritis has become more common, and several surgical procedures have demonstrated pain relief and improved hip joint function. Periacetabular osteotomy, one of the joint-preserving surgical procedures of the hip, provides favorable outcomes, although there are no reports of total hip arthroplasty being used to treat pseudoarthrosis of the periacetabular osteotomy segment. Therefore, we report a case of pseudoarthrosis in the osteotomy segment after periacetabular osteotomy. The patient was treated using modified total hip arthroplasty and achieved a favorable short-term outcome. Case presentation A 62-year-old Japanese woman was diagnosed with bilateral acetabular dysplasia at the age of 50 years, and underwent right and left periacetabular osteotomy at the ages of 52 and 55 years, respectively. When she was 61-years old, she experienced repeated episodes of left coxalgia during walking, with increasing pain at rest, and subsequently visited our department. Plain radiography and computed tomography of her left hip joint confirmed pseudoarthrosis of the periacetabular osteotomy segment. In addition, narrowing of her left hip joint space was observed, which indicated advanced osteoarthritis of the hip. Therefore, she underwent left total hip arthroplasty when she was 62-years old. During the surgery, fibrous fusion of the periacetabular osteotomy segment was confirmed via fluoroscopy, although no abnormal mobility was observed. Thus, the osteotomy segment was fixed with one absorbable screw and two bone pegs (which were prepared using allogeneic bone), and the acetabular cup was fixed using cement. Her postoperative course was generally favorable and bone fusion of the periacetabular osteotomy segment was confirmed at 3 years and 6 months after surgery. Her modified Harris hip score was 43 before the surgery and had improved to 90 at the final follow-up. Conclusions Modified total hip arthroplasty was successfully used to treat osteoarthritis of the hip and pseudoarthrosis of the periacetabular osteotomy segment. This procedure achieved pseudoarthrosis region bone fusion and a favorable postoperative outcome.

Bone mass is tightly controlled by a balance between osteoclast and osteoblast activities. Although these cell types mature via different pathways, some factors reportedly regulate differentiation of both. Here, in a search for factors governing osteoblastogenesis but also expressed in osteoclasts to control both cell types by one molecule, we identified B cell lymphoma 6 (Bcl6) as one of those factors and show that it promotes osteoblast differentiation. Bcl6 was previously shown to negatively regulate osteoclastogenesis. We report that lack of Bcl6 results in significant inhibition of osteoblastogensis in vivo and in vitro and in defects in secondary ossification center formation in vivo. Signal transducer and activator of transcription 1 (Stat1) reportedly attenuates osteoblast differentiation by inhibiting nuclear translocation of runt-related transcription factor 2 (Runx2), which is essential for osteoblast differentiation. We found that lack of Bcl6 resulted in significant elevation of Stat1 mRNA and protein expression in osteoblasts and showed that Stat1 is a direct target of Bcl6 using a chromatin immune-precipitation assay. Mice lacking both Bcl6 and Stat1 (DKO) exhibited significant rescue of bone mass and osteoblastic parameters as well as partial rescue of secondary ossification center formation compared with Bcl6-deficient mice in vivo. Altered osteoblastogenesis in Bcl6-deficient cells was also restored in DKO in vitro. Thus, Bcl6 plays crucial roles in regulating both osteoblast activation and osteoclast inhibition.

Neonatal gene transfer using adenovirus vectors expressing human beta-glucuronidase (AxCAhGUS) resulted in pathological improvement in multiple visceral organs of mice with mucopolysaccharidosis type VII (MPSVII). However, the therapeutic effect on skeletal deformities and growth retardation, the major clinical symptoms in MPSVII, was not fully investigated by biochemical and histopathological analyses. In this study, we injected AxCAhGUS into a murine model of MPSVII (B6/MPSVII) within 24 h of birth and evaluated the therapeutic effects on skeletal deformities and growth retardation. High levels of beta-glucuronidase (GUSB) activity (approximately threefold higher than normal GUSB activity) were observed in the articular cartilage of the mice 30 days after the treatment. Histopathological study in the knee joints showed elimination of vacuole cells in the articular cartilage and growth plate. Subchondral bone near the articular surface was almost normal in the treated MPSVII mice. Long-term observation (for 140 days after treatment) indicated that characteristic phenotypes such as flattened face, hunched stature, and shortening of bone length in the treated mice were almost normal. These results demonstrate that a single injection of adenovirus vector into neonatal MPSVII mice is sufficient for long-term normalization of skeletal deformities and effective in pathological correction of the articular cartilage and growth plate.

Introduction It has been well documented that labral tear is frequently associated with femoroacetabular impingement and dysplasia of the hip; however, there have been few reported cases of labral tear associated with idiopathic osteonecrosis of the hip. Here we report the case of a patient with labral tear associated with idiopathic osteonecrosis of the femoral head who was treated by hip arthroscopy, with a favorable short-term outcome. Case presentation Under the diagnosis of systemic lupus erythematosus, a 28-year-old Japanese woman was treated with the oral administration of steroid in 2007. A year after the treatment, she developed right hip joint pain and was diagnosed with idiopathic osteonecrosis of the femoral head at our institution. In November of 2011, she revisited our hospital when her right hip joint pain exacerbated and she became unable to walk. On the visit, the anterior impingement sign and Patrick test were positive. Radiography and magnetic resonance imaging in 2011 demonstrated neither spreading of the osteonecrosis area nor collapse of the femoral head in the right joint; however, magnetic resonance imaging showed a high-intensity area in the articular labrum in a T2-weighted image, leading to a diagnosis of labral tear. She underwent labral repair with hip arthroscopy in August of 2012. Now, 1 year after surgery, she does not feel any pain during walking and her modified Harris hip score has improved from 20 prior to surgery to 85. Conclusion The case indicated that it is important to be aware of the possibility of labral tear in patients with idiopathic osteonecrosis of the femoral head, when spreading of the osteonecrosis area or collapse of the femoral head has not been seen on magnetic resonance imaging.

Background Metal-on-metal prostheses undergo wear and corrosion, releasing soluble ions and wear particles into the surrounding environment. Reports described early failures of the metal-on-metal prostheses, with histologic features similar to a Type IV immune response. Mechanisms by which metal wear products and metal ion causing this reaction are not completely understood, and the effects of metal ions on osteocytes, which represent more than 95% of all the bone cells, have not been also studied. We hypothesized that soluble metal ions released from the cobalt-chromium-molybdenum (Co-Cr-Mo) prosthesis may have cytotoxic effect on osteocytes. Methods MLO-Y4 osteocytes were treated with various metal ion solutions for 24 and 48 h. The effect of ion treatment on cytotoxicity was assessed by WST-1 reagents and cell death ELISA. Morphological changes were analyzed by a phase-contrast microscope or fluorescent microscope using Hoechst 33342 and propidium iodine staining. Results Cr and Mo ions did not cause cell death under 0.50 mM, highest concentration studied, whereas Co and Ni ions had significant cytotoxic effect on MLO-Y4 cells at concentrations grater than 0.10 mM and at 0.50 mM, respectively, in a dose-dependent manner. According to the ELISA data, osteocytes treated with Co ions were more susceptible to necrotic than apoptotic cell death, while Ni ions caused osteocyte apoptosis. The morphological assays show that cells treated with Co and Ni ions at high concentration were fewer in number and rounded. In addition, fluorescent images showed a marked reduction in live cells and an increase in dead osteocytes treated with Co and Ni ions at high concentration. Conclusions Metal ions released from metal-on-metal bearing surfaces have potentially cytotoxic effects on MLO-Y4 osteocytes, in vitro.

Interleukin (IL)-1 is one of the most evolutionarily conserved cytokines and plays an essential role in the regulation of innate immunity. IL-1 binds to two different receptors, IL-1R1 and IL-1R2, which share approximately 28% amino acid homology. IL-1R1 contains a cytoplasmic domain and is capable of transducing cellular signals; by contrast, IL-1R2 lacks a functional cytoplasmic domain and serves as a decoy receptor for IL-1. Interestingly, IL-1R2 is proteolytically cleaved and also functions as a soluble receptor that blocks IL-1 activity. In the present study, we examined the shedding properties of IL-1R2 and demonstrate that ADAM17 is de facto the major sheddase for IL-1R2 and that introducing a mutation into the juxta-membrane domain of IL-1R2 significantly desensitizes IL-1R2 to proteolytic cleavage. IL-1R1 was almost insensitive to ADAM17-dependent cleavage; however, the replacement of the juxta-membrane domain of IL-R1 with that of IL-1R2 significantly increased the sensitivity of IL-1R1 to shedding. Furthermore, we demonstrate that ADAM17 indirectly enhances IL-1 signaling in a cell-autonomous manner by selectively cleaving IL-1R2. Taken together, the data collected in the present study indicate that ADAM17 affects sensitivity to IL-1 by changing the balance between IL-1R1 and the decoy receptor IL-1R2.

Recent advances in systemic treatments for mucopolysaccharidosis have led to therapies that improve the multiple somatic features of this disease, but the therapeutic effect on ocular manifestations such as corneal clouding is not satisfactory. Here, we administered an adenovirus expressing human beta-glucuronidase (AxCAhGUS) into the anterior chamber or intrastromal region of the cornea in mice with mucopolysaccharidosis type VII (B6/MPSVII), and successfully treated corneal clouding of MPSVII. When we injected AxCAhGUS into the anterior chamber of the eyes, cells expressing beta-glucuronidase (GUSB) were located mainly in the trabecular meshwork as well as in all corneal regions, and subsequent pathological corrections in the cornea were achieved. Widespread transgene expression was also observed when we administered AxCAhGUS inside the cornea after lamellar keratotomy, and rapid elimination of the lysosomal storage in the corneal keratocytes occurred. Furthermore, intrastromal vector administration did not generate significant levels of anti-adenovirus neutralizing antibodies, and secondary vector administration was effective. Based on these observations, we conclude that it is worth developing a treatment strategy for corneal clouding in mucopolysaccharidosis based on direct intraocular administration of adenoviral vectors.

Heterotopic ossification (HO) is defined as the formation of ectopic bone in soft tissue outside the skeletal tissue. HO is thought to result from aberrant differentiation of osteogenic progenitors within skeletal muscle. However, the precise origin of HO is still unclear. Skeletal muscle contains two kinds of progenitor cells, myogenic progenitors and mesenchymal progenitors. Myogenic and mesenchymal progenitors in human skeletal muscle can be identified as CD56(+) and PDGFRα(+) cells, respectively. The purpose of this study was to investigate the osteogenic differentiation potential of human skeletal muscle-derived progenitors. Both CD56(+) cells and PDGFRα(+) cells showed comparable osteogenic differentiation potential in vitro. However, in an in vivo ectopic bone formation model, PDGFRα(+) cells formed bone-like tissue and showed successful engraftment, while CD56(+) cells did not form bone-like tissue and did not adapt to an osteogenic environment. Immunohistological analysis of human HO sample revealed that many PDGFRα(+) cells were localized in proximity to ectopic bone formed in skeletal muscle. MicroRNAs (miRNAs) are known to regulate many biological processes including osteogenic differentiation. We investigated the participation of miRNAs in the osteogenic differentiation of PDGFRα(+) cells by using microarray. We identified miRNAs that had not been known to be involved in osteogenesis but showed dramatic changes during osteogenic differentiation of PDGFRα(+) cells. Upregulation of miR-146b-5p and -424 and downregulation of miR-7 during osteogenic differentiation of PDGFRα(+) cells were confirmed by quantitative real-time RT-PCR. Inhibition of upregulated miRNAs, miR-146b-5p and -424, resulted in the suppression of osteocyte maturation, suggesting that these two miRNAs have the positive role in the osteogenesis of PDGFRα(+) cells. Our results suggest that PDGFRα(+) cells may be the major source of HO and that the newly identified miRNAs may regulate osteogenic differentiation process of PDGFRα(+) cells.

Aseptic loosening is the devastating long term complication of total hip arthroplasty and orthopedic implant debris has been shown to trigger an intense inflammatory reaction leading to resorption of the bone matrix. Inflammatory cytokines, such as tumor necrosis factor-α (TNFα), have been implicated in this process and osteocytes may play a role in its production. We previously demonstrated that cobalt-chromium-molybdenum (CoCrMo) particles upregulate TNFα production by MLO-Y4 osteocytes in vitro, but the underlying mechanism has not been elucidated. Based on previous studies by others, we hypothesized that the calcineurin-nuclear factor of activated T cells (NFAT) pathway mediates CoCrMo particle-induced TNFα production in MLO-Y4 osteocytes. MLO-Y4 osteocytes exposed to CoCrMo particle treatment resulted in a rapid and significant increase in calcineurin activity. We also demonstrate that CoCrMo particle-induced upregulation of TNFα is reduced to control levels with calcineurin-NFAT inhibitors and this was also confirmed at mRNA level. Moreover, we demonstrate the localization of NFATs in MLO-Y4 osteocytes and that NFAT1 and 2 translocate to the nucleus upon CoCrMo particle treatment. Our results suggest that calcineurin-NFAT signaling is involved in TNFα production by MLO-Y4 osteocytes after CoCrMo particle treatment.

Low-intensity pulsed ultrasound (LIPUS) is an established therapy for fracture repair and has been used widely in the clinics, but its underlying mechanism of action remains unclear. The aim of the current research was to determine the effect of LIPUS on gap junctional cell-to-cell intercellular communication in rat bone marrow stromal cells (BMSC) in vitro and to determine whether the ability of BMSCs to communicate by gap junctions would affect their response to LIPUS. Single or daily-multiple LIPUS treatment at 1.5 MHz, 30 mW/cm2, for 20 min was applied to BMSC. We demonstrated that BMSC form functional gap junctions and single LIPUS treatment significantly increased the intracellular dye transfer between BMSC. In addition, activated phosphorylation of ERK1/2 and p38 by LIPUS stimulation was diminished when cells were treated with a gap junction inhibitor 18β-glycyrrhetinic acid (18β). We further demonstrated that 18β diminished the significant increase in alkaline phosphatase activity following LIPUS stimulation. These results suggest a potential role of gap junctional cell-to-cell intercellular communication on the effects of LIPUS in BMSC.

Biological markers for osteoarthritis (OA) are indicators of articular tissue metabolism, measuring the levels of molecules derived from joint structures into synovial fluids, serum and urine. Radiological findings are the basis of diagnosis of OA, but have a weakpoint visualizing the figures that have already occurred. For assessing disease activity or monitoring disease progression, estimation of articular metabolism using biological markers is very important. Synovial fluid reflects specifically the status of the punctured joint, however invasive. Less-invasive newly developed serum and urine markers appear to be also useful for the evaluation of OA.

The possibility of predicting the effectiveness of intraarticular injection of high molecular weight hyaluronan (HA) was investigated using biological markers.In 32 patients with osteoarthritis (OA) of the knee, 38 knees were treated with HA injection, and the clinical symptoms were evaluated using the Japanese Orthopaedic Association (JOA) score and pain visual analog scale (VAS). The concentrations of chondroitin 6-sulfate, 4-sulfate (C6S, C4S), and aggrecan were measured in synovial fluid collected at the time of initiation of injection. The relationship between the biological markers and the improvement of clinical symptoms after injection for 1 month was investigated.C6S/C4S and concentration of aggrecan decreased after injection, although these decreases were not significant. Positive correlations were noted between the concentrations of C6S and aggrecan before HA injection and the improvement of the JOA score after injection; however, radiological OA stage had no significant relation with improvement both of the JOA score and VAS.It has been reported that the concentration of aggrecan-derived fragments in synovial fluid decreases with advancement of the OA stage, reflecting decreases in the amount of residual cartilage and suppression of chondrocyte metabolism. Our findings suggested that HA injection exhibits a greater clinical effect in cases with a high intraarticular aggrecan fragment concentration, i.e., cases in which a high amount of residual cartilage and chondrocyte metabolic activity remain. The biological markers were useful in predicting the effectiveness of HA injection for OA of the knee.

There is no well-established treatment for osteoporosis in male patients with leprosy, because no clinical trials have examined the efficacy of treatment on bone mineral density (BMD) or fracture incidence in such patients. The purpose of the present study was to evaluate the therapeutic effect on oral administration of risedronate in male osteoporotic patients with leprosy. Twenty-three male patients with leprosy, 63-87 years of age, were randomly divided into two administration groups: R group (risedronate, 2.5 mg/day, daily) and P group (placebo, daily). The BMD of the lumbar spine (L2-L4) was measured by dual-energy X-ray absorptiometry, and urinary cross linked N-telopeptides of type I collagen (NTX) were assessed at baseline, 6 months, and 12 months after treatment. There were no significant differences in age, body mass index, BMD, or urinary NTX levels at baseline between the two groups. In the present study, oral administration of risedronate apparently prevented vertebral fractures by increasing lumbar BMD and caused a significant reduction in urinary NTX levels, while oral administration of placebo did not increase the lumbar BMD and prevent vertebral fractures due to osteoporosis. The above findings suggested that oral administration of risedronate contributed to the prevention of vertebral fractures by suppressing bone resorption and increasing in lumbar BMD in the elderly male patients with leprosy.

Insufficiency fracture following total hip arthroplasty (THA) frequently occurs in the superior and inferior pubic ramus, the puboischial rami, or the ischium around the obturator foramen, while it rarely occurs in the medial wall of the acetabulum. Here, we report three cases showing insufficiency fracture in the medial wall of the acetabulum following THA. In our three cases, two fractures resulted from the development of bone fragility due to osteolysis at the prosthesis site, and the convergence of mechanical stress on the acetabular load bearing point due to loosening of the cup. We consider it appropriate to describe these fractures as another entity of stress fracture, namely, osteolytic fracture, rather than either pathologic fracture or insufficiency fracture.