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Introduction: Exercise intensity determines the benefits of aerobic exercise. Our objectives were, in aerobic exercise at different intensities, to determine (1) changes in bone metabolism-related genes after acute exercise and (2) changes in bone mass, strength, remodeling, and bone formation-related proteins after long-term exercise. Materials and methods: Total 36 male C57BL/6J mice were divided into a control group and exercise groups at 3 different intensities: low, moderate, or high group. Each exercise group was assigned to acute- or long-term exercise groups. Tibias after acute exercise were evaluated by real-time PCR analysis. Furthermore, hindlimbs of long-term exercise were assessed by micro-CT, biomechanical, histological, and immunohistochemical analyses. Results: Acute moderate-intensity exercise decreased RANKL level as bone resorption marker, whereas low- and high-intensity exercise did not alter it. Additionally, only long-term exercise at moderate intensity increased bone mass and strength. Moderate-intensity exercise promoted osteoblast activity and suppressed osteoclast activity. After low- and high-intensity exercise, osteoblast and osteoclast activity were unchanged. An increase in the number of β-catenin-positive cells and a decrease in sclerostin-positive cells were observed in the only moderate group. Conclusion: These results showed that moderate-intensity exercise can inhibit bone resorption earlier, and long-term exercise can increase bone mass and strength through promoted bone formation via the Wnt/β-catenin activation. High-intensity exercise, traditionally considered better for bone, may fail to stimulate bone remodeling, leading to no change in bone mass and strength. Our findings suggest that moderate-intensity exercise, neither too low nor high, can maintain bone health. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury causes long-term motor dysfunction. Ultrasound (US) therapy is expected to accelerate peripheral nerve regeneration. However, its optimal usage and effects on macrophage phenotypes during peripheral nerve regeneration remain unknown. In this study, we investigated the optimal duration of US therapy and its effects on macrophage phenotype. Twenty-seven rats with autologous sciatic nerve grafting were divided into three groups: two received US therapy (1 MHz frequency, intensity of 140 mW/cm2, 20% duty cycle, 5 min/day) for one (US1) or 4 weeks (US4), and one group received sham stimulation. Immunohistochemistry was performed 3 and 7 days after injury in another set of 12 rats. Eight weeks after the injury, the compound muscle action potential amplitude of the gastrocnemius in the US1 and US4 groups was significantly higher than that in the sham group. The toe-spreading test showed functional recovery, whereas the gait pattern during treadmill walking did not recover. There were no significant differences in motor function, histomorphometry, or muscle weight between groups. Immunohistochemistry showed that US therapy decreased the number of pro-inflammatory macrophages seven days after injury. Therefore, US therapy for both one or 4 weeks can similarly promote reinnervation and reduce proinflammatory macrophages in autograft model rats. [ABSTRACT FROM AUTHOR]

With the increasing demand for energy-saving technologies, neodymium-iron-boron magnets have been widely utilized in high-efficiency motors. However, the reserves of neodymium, which is a rare earth element (REE), are limited; thus, a strategy for scaling up the REE supply is highly required. In this study, a scenario assessment was conducted to evaluate the effect of material recycling of neodymium from final product waste. Domestic substance flow analysis of neodymium was conducted by focusing on the waste flow of the final product. Moreover, the demand and waste of neodymium until 2050 were forecasted using various multivariate analysis methods. The results showed that the domestic waste of neodymium was forecasted to be 3866–4217 tons/year by 2050. However, material recycling of neodymium from final product waste may cause an additional increase in production by "circular economy rebound". Considering that CO2 reduction has also been a global challenge to prevent global warming, the rebound effect was calculated. Therefore, a scenario assessment was conducted to evaluate the influence of this rebound effect by estimating the CO2 reduction. The results of this study are expected to make a significant contribution to the establishment of a new strategy for neodymium recycling. [ABSTRACT FROM AUTHOR]

Tendon self-renewal is a rare occurrence because of the poor vascularization of this tissue; therefore, reconstructive surgery using autologous tendon is often performed in severe injury cases. However, the post-surgery re-injury rate is relatively high, and the collection of autologous tendons leads to muscle weakness, resulting in prolonged rehabilitation. Here, we introduce an induced pluripotent stem cell (iPSC)-based technology to develop a therapeutic option for tendon injury. First, we derived tenocytes from human iPSCs by recapitulating the normal progression of step-wise narrowing fate decisions in vertebrate embryos. We used single-cell RNA sequencing to analyze the developmental trajectory of iPSC-derived tenocytes. We demonstrated that iPSC-tenocyte grafting contributed to motor function recovery after Achilles tendon injury in rats via engraftment and paracrine effects. The biomechanical strength of regenerated tendons was comparable to that of healthy tendons. We suggest that iPSC-tenocytes will provide a therapeutic option for tendon injury. Tendon self-renewal occurs rarely and reconstructive surgery comes with significant limitations. Here the authors present an induced pluripotent stem cell-based method to generate tenocytes, analyze their developmental trajectory using scRNA-seq, and demonstrate their contribution to motor function recovery after Achilles tendon injury via engraftment and paracrine effects. [ABSTRACT FROM AUTHOR]

Current treatment options for osteoporosis primarily involve pharmacotherapies, but they are often accompanied by undesirable side effects. Utilization of mechanical stress which can noninvasively induce bone formation has been suggested as an alternative to conventional treatments. Here, we examined the efficacy of mechanical stress induced by electrical stimulation, radial extracorporeal shock waves, and ultrasound for estrogen-deficient osteoporosis. Female Wistar rats were divided into following five groups: sham-operated group, untreated after ovariectomy, and treated with electrical stimulation, radial extracorporeal shock wave, or ultrasound starting at 8 weeks after ovariectomy for 4 weeks. Trabecular bone architecture of the femur was assessed by micro-CT and its biomechanical properties were obtained by mechanical testing. The femurs were further evaluated by histochemical, immunohistochemical, and real-time PCR analyses. Radial extracorporeal shock wave and ultrasound treatment improved trabecular bone microarchitecture and bone strength in osteoporotic rats, but not electrical stimulation. The shock wave decreased osteoclast activity and RANKL expression. The exposure of ultrasound increased osteoblast activity and β-catenin-positive cells, and they decreased sclerostin-positive osteocytes. These findings suggest that mechanical stress induced by radial extracorporeal shock wave and ultrasound can improve estrogen-deficient bone loss and bone fragility through promoted bone formation or attenuated bone resorption. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

Accelerated fracture healing in patients with spinal cord injuries (SCI) is often encountered in clinical practice. However, there is no distinct evidence in the accelerated fracture healing, and the mechanisms of accelerated fracture healing in SCI are poorly understood. We aimed to determine whether SCI accelerated fracture healing in morphology and strength, to characterize the healing process with SCI, and to clarify the factors responsible for accelerated fracture healing. In total, 39 male Wistar rats were randomly divided into healthy control without intervention, SCI only, fracture with SCI, botulinum toxin (BTX) A-treated fracture with SCI, and propranolol-treated fracture with SCI groups. These rats were assessed with computed microtomography, histological, histomorphological, immunohistological, and biomechanical analyses. Both computed microtomography and histological analyses revealed the acceleration of a bony union in animals with SCI. The strength of the healed fractures after SCI recovered to the same level as that of intact bones after SCI, while the healed bones were weaker than the intact bones. Immunohistology revealed that SCI fracture healing was characterized by formation of callus with predominant intramembranous ossification and promoting endochondral ossification. The accelerated fracture healing after SCI was attenuated by BTX injection, but did not change by propranolol. We demonstrated that SCI accelerate fracture healing in both morphology and strength. The accelerated fracture healing with SCI may be due to predominant intramembranous ossification and promoting endochondral ossification. In addition, our results also suggest that muscle contraction by spasticity accelerates fracture healing after SCI. [ABSTRACT FROM AUTHOR]

Although osteochondral grafting surgery is believed to replace damaged cartilage with healthy-looking normal cartilage, no study focuses on ultrasound quantification of those cartilage immediately after the surgery. It is unknown whether the ultrasound properties of damaged cartilage from trauma or osteonecrosis are same with each other. We have examined ultrasound properties of damaged cartilage, adjacent intact cartilage and plug cartilage during osteochondral grafting surgery for 15 knees of 15 patients, mean age of 43.4 (range, 14–61) years. Results showed that signal intensities of ultrasound (a measure of superficial cartilage integrity) of intact cartilage, damaged cartilage, and plug cartilage were 1.91 (arbitrary unit), 0.40, and 2.13, respectively, in 11 knees of 11 patients of traumatic cartilage lesions. Interval between signals of ultrasound (a parameter related to thickness) were 2.79 (μs), 1.90, and 2.85, respectively. The signal intensity and the interval between signals of plug cartilage were 533% ( P < 0.01) and 150% ( P < 0.01) of damaged cartilage, respectively. In four knees of four patients of osteonecrosis, the signal intensities of intact cartilage, damaged cartilage, and plug cartilage were 1.25, 0.30, and 1.39, respectively. The interval between signals were 2.36, 2.00, and 2.69, respectively. The signal intensity and the interval between signals of plug cartilage were 463% ( P < 0.01) and 135% ( P < 0.05) of damaged cartilage. We conclude that ultrasound properties of the damaged cartilage from trauma or osteonecrosis did not differ a lot especially in the late stages of osteonecrosis and that the osteochondral grafting surgery replaced the damaged cartilage with plug cartilage that had greater superficial cartilage integrity and greater thickness parameter immediately after the surgery. Long-term effect of the osteochondral grafting surgery should be verified in further study. [ABSTRACT FROM AUTHOR]

Although grafted osteochondral plugs should ideally have a smooth surface for mosaicplasty, surface incongruity is sometimes evident at the time of surgery. There may be no problem if there is depression of the grafted plugs, but graft protuberance may have an adverse effect. We studied five knees in five patients who had incongruity (protuberance or depression) of grafted osteochondral plugs at the time of mosaicplasty. The mean age at surgery was 36.6 years (range, 15–65 years), and the mean follow-up period was 32.9 months (range, 24–49 months). All patients underwent second-look arthroscopy after a mean post-surgical period of 14.8 months (range, 3–18 months). We divided the cases so that there were two in the protuberant group (P) and three in the depressed group (D). In P, all patients had a catching sensation about 4 months after surgery, and sometimes pain in the knee joint. Second-look arthroscopy revealed fissuring of the plugs and fibrillation around the recipient site. In D, there were no symptoms due to the depressed plugs. Second-look arthroscopy showed that the depressed areas were covered with fibrocartilage-like tissue, and that the joint surface was smooth. In conclusion, our clinical results and second-look arthroscopic evaluation suggest that isolated osteochondral plug depressions of not greater than 1 mm could still promote acceptable cartilage healing leading to good clinical outcomes. However, plug protuberance at mosaicplasty should always be avoided. [ABSTRACT FROM AUTHOR]

A correction to this paper has been published: https://doi.org/10.1007/s00223-021-00867-8 [ABSTRACT FROM AUTHOR]

Post-traumatic osteoarthritis (PTOA) is a major cause which hinders patients from the recovery after intra-articular injuries or surgeries. Currently, no effective treatment is available. In this study, we showed that inhibition of the acute stage chondrocyte death is a promising strategy to mitigate the development of PTOA. Namely, we examined efficacies of Kyoto University Substance (KUS) 121, a valosin-containing protein modulator, for PTOA as well as its therapeutic mechanisms. In vivo, in a rat PTOA model by cyclic compressive loading, intra-articular treatments of KUS121 significantly improved the modified Mankin scores and reduced damaged-cartilage volumes, as compared to vehicle treatment. Moreover, KUS121 markedly reduced the numbers of TUNEL-, CHOP-, MMP-13-, and ADAMTS-5-positive chondrocytes in the damaged knees. In vitro, KUS121 rescued human articular chondrocytes from tunicamycin-induced cell death, in both monolayer culture and cartilage explants. It also significantly downregulated the protein or gene expression of ER stress markers, proinflammatory cytokines, and extracellular-matrix-degrading enzymes induced by tunicamycin or IL-1β. Collectively, these results demonstrated that KUS121 protected chondrocytes from cell death through the inhibition of excessive ER stress. Therefore, KUS121 would be a new, promising therapeutic agent with a protective effect on the progression of PTOA. [ABSTRACT FROM AUTHOR]

This systematic review with a meta-analysis aimed to summarize the current evidence of the effectiveness of mesenchymal stem cell (MSC) treatment for knee osteoarthritis (OA) and to examine whether rehabilitation is an effect modifier of the effect estimate of MSC treatment. A literature search yielded 659 studies, of which 35 studies met the inclusion criteria (n = 2385 patients; mean age: 36.0–74.5 years). The meta-analysis results suggested that MSC treatment through intra-articular injection or arthroscopic implantation significantly improved knee pain (standardized mean difference [SMD]: −1.45, 95% confidence interval [CI]: −1.94, −0.96), self-reported physical function (SMD: 1.50, 95% CI: 1.09, 1.92), and cartilage quality (SMD: −1.99; 95% CI: −3.51, −0.47). However, the MSC treatment efficacy on cartilage volume was limited (SMD: 0.49; 95% CI: −0.19, 1.16). Minor adverse events (knee pain or swelling) were reported with a wide-ranging prevalence of 2–60%; however, no severe adverse events occurred. The evidence for these outcomes was "very low" to "low" according to the Grades of Recommendation, Assessment, Development and Evaluation system because of the poor study design, high risk of bias, large heterogeneity, and wide 95% CI of the effects estimate. Performing rehabilitation was significantly associated with better SMD for self-reported physical function (regression coefficient: 0.881, 95% CI: 0.049, 1.712; P = 0.039). We suggest that more high quality randomized controlled trials with consideration of the potential rehabilitation-driven clinical benefit would be needed to facilitate the foundation of effective MSC treatment and regenerative rehabilitation for patients with knee OA. [ABSTRACT FROM AUTHOR]