Review of the Molecular Pathogenesis of Osteosarcoma Osteosarcoma;pathogenesis;genetic factors;chemotherapy resistance; Treating the osteosarcoma (OSA) remains a challenge. Current strategies focus on the primary tumor and have limited efficacy for metastatic OSA. A better understanding of the OSA pathogenesis may provide a rational basis for innovative treatment strategies especially for metastases. The aim of this review is to give an overview of the molecular mechanisms of OSA tumorigenesis, OSA cell proliferation, apoptosis, migration, and chemotherapy resistance, and how improved understanding might contribute to designing a better treatment target for OSA.

Osteoblasts and osteoclasts participate in the process of bone remodelling to meet the needs of normal growth and development or repair pathological damage. Endoplasmic reticulum stress (ER stress) can break the intracellular homeostasis of osteoclasts and osteoblasts, which is closely related to abnormal bone remodelling. The double‐stranded RNA‐dependent protein kinase (PKR)‐like ER kinase (PERK) is a key transmembrane protein that regulates ER stress, and growing evidence suggests that the PERK pathway plays a crucial role in regulating bone metabolism under both physiological and pathological conditions. Based on the current findings, we summarized the main mechanisms involved in bone metabolism downstream of the PERK pathway, among which elF2α, FOXO1, CaN, Nrf2 and DAG play a role in regulating the differentiation of osteoblasts and osteoclasts. Importantly, strategies by the regulation of PERK pathway exert beneficial effects in preclinical trials of several bone‐related diseases. Given the importance and novelty of PERK pathway, we provide an overview and discuss the roles of PERK pathway in regulating bone metabolism and its impact on bone‐related diseases. We hope that the development of research in this field will bring a bright future for the treatment of bone‐related diseases.

Objective: Various methods are applied in the clinical treatment of idiopathic clubfoot. The purpose of this meta-analysis was to evaluate the efficacy of different conservative treatments. Methods: Studies were pooled and odds ratio (ORs) with corresponding confidence intervals were calculated for evaluation of the results, relapses, and requirement for major surgery. Results: A final analysis of 1435 patients from 9 eligible studies was performed. The combined OR indicated that significantly more fair and poor results were achieved and that major surgery was required significantly more often when using non-Ponseti’s methods (OR = 3.33 and OR = 7.32, respectively), but no significant difference was detected in the occurrence of relapse (OR = 1.34). Pooled OR evaluation showed a significantly higher rate of fair and poor results, relapse, and requirement for major surgery when using Kite’s method than when using Ponseti’s method (OR = 3.93, OR = 2.53, and OR = 3.19, respectively), but no significant difference was detected between the French method and Ponseti’s method (OR = 3.01, OR = 0.72, and OR = 1.26, respectively). Conclusions: This meta-analysis indicates that Ponseti’s method is safe and efficient for conservative treatment of clubfoot and decreases the number of surgical interventions required. It is recommended as the first-choice conservative treatment for idiopathic clubfoot.

Objective According to the current treatment protocol of the Cooperative Osteosarcoma Study, it is mandatory to determine the histological response to neoadjuvant chemotherapy treatment before surgical removal of the tumor, particularly if a limb salvage procedure is planned. The aim of this systematic, retrospective study was to evaluate the ability of 2‐(¹⁸F) fluoro‐2‐deoxy‐D‐glucose positron‐emission tomography/computed tomography to predict chemotherapy response of osteosarcoma and to identify a simple promising method for noninvasive evaluation of neoadjuvant chemotherapy response in osteosarcoma. Methods The PubMed database was searched to identify and analyze relevant published reports. In particular, correlations between tumor‐to‐background ratio (TBR), standard uptake value (SUV) and histological response to chemotherapy were assessed. Results It was found that good responses are achieved in patients with TBR after chemotherapy (TBR2)/TBR before chemotherapy (TBR1) < 0.470 (positive predictive value [PPV] = 92.31%, negative predictive value [NPV] = 82.76%, sensitivity [S] = 87.80%, specificity [SP] = 88.89%), whereas poor responses occur in patients with SUV after chemotherapy/before chemotherapy (SUV2/SUV1) > 0.396 (PPV = 73.68%, NPV = 73.33%, S = 63.64%, SP = 81.48%). Conclusion Changes in TBR are better predictors of chemotherapy response than SUV in osteosarcoma patients. Therefore, we believe that choice of surgical strategy is optimally based on changes in TBR.

Osteoporosis is a systemic and endocrine bone disorder distinguished by declined bone mineral density, compromised bone strength, and destruction of trabecular structure. The abnormally excessive osteoclastogenesis and bone erosion play imperative roles in the progression of osteoporosis. However, treatment of osteoporosis is far from satisfactory due to poor adherence to existing medications and adverse reactions, there is an urgent to develop novel therapies for osteoporosis. Probucol, a synthetic compound with two characteristic phenolic rings, owns anti-inflammatory and antioxidant properties. Accumulating evidence have indicated that intracellular reactive oxygen species (ROS) is closely related to osteoclastogenesis. Hence, we investigated the potential effects of probucol on osteoclastogenesis in vivo and in vitro. In this study, TRAP staining and bone slice resorption assay showed that probucol suppressed RANKL-induced osteoclast formation and function. The mRNA and protein levels of osteoclastogenesis marker genes were reduced by probucol in a concentration-dependent manner. Besides, probucol suppressed osteoclast differentiation by inhibiting ROS production, MAPKs and NF-κB signaling pathways, while Nrf2 silencing reversed the inhibitory effect of probucol on osteoclast formation and function. Consistent with the above findings, in vivo experiments demonstrated that probucol visibly alleviated bone loss caused by estrogen deficiency. In brief, these results showed the potential of anti-oxidant compound probucol in the treatment of osteoporosis, highlighting Nrf2 as a promising target in osteoclast-related disease.