Gut Clostridium sporogenes-derived indole propionic acid suppresses osteoclast formation by activating pregnane X receptor.

Bone homeostasis is maintained by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. A dramatic decrease in estrogen levels in postmenopausal women leads to osteoclast overactivation, impaired bone homeostasis, and subsequent bone loss. Changes in the gut microbiome affect bone mineral density. However, the role of the gut microbiome in estrogen deficiency-induced bone loss and its underlying mechanism remain unknown. In this study, we found that the abundance of Clostridium sporogenes (C. spor.) and its derived metabolite, indole propionic acid (IPA), were decreased in ovariectomized (OVX) mice. In vitro assays suggested that IPA suppressed osteoclast differentiation and function. At the molecular level, IPA suppressed receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced pregnane X receptor (PXR) ubiquitination and degradation, leading to increased binding of remaining PXR with P65. In vivo daily IPA administration or repeated C. spor. colonization protected against OVX-induced bone loss. To protect live bacteria from the harsh gastric environment and delay the emptying of orally administered C. spor. from the intestine, a C. spor.-encapsulated silk fibroin (SF) hydrogel system was developed, which achieved bone protection in OVX mice comparable to that achieved with repeated germ transplantation or daily IPA administration. Overall, we found that gut C. spor.-derived IPA was involved in estrogen deficiency-induced osteoclast overactivation by regulating the PXR/P65 complex. The C. spor.-encapsulated SF hydrogel system is a promising tool for combating postmenopausal osteoporosis without the disadvantages of repeated germ transplantation.

Cancer-Erythrocyte Membrane-Mimicking Fe3O4 Nanoparticles and DHJS for Ferroptosis/Immunotherapy Synergism in Tumors.

Ferroptosis is characterized by iron accumulation and lipid peroxidation. However, a clinical dose of Fe3O4 nanoparticles could not cause effective ferroptosis in tumors, and the mechanism is yet to be completely understood. In this study, using RNA-seq data, we found that tumor cells could feedback-activate the antioxidant system by upregulating Nrf-2 expression, thus avoiding ferroptosis caused by Fe3O4 nanoparticles. We also found that DHJS (a probe for ROS generation) can antagonize Nrf-2 expression when it synergizes with Fe3O4 nanoparticles, thus inducing ferroptosis in tumor cells. Considering these findings, we created a biomimetic hybrid cell membrane camouflaged by PLGA-loaded Fe3O4 and DHJS to treat osteosarcoma. The hybrid cell membrane endowed the core nanoparticle with the extension of blood circulation life and enhanced homologous targeting ability. In addition, DHJS and Fe3O4 in nanoparticles prompted synergistically lethal ferroptosis in cancer cells and induced macrophage M1 polarization as well as the infiltration of CD8(+) T cells and dendritic cells in tumors. In summary, this study provides novel mechanistic insights and practical strategies for ferroptosis induction of Fe3O4 nanoparticles. Meanwhile, the synthesized biomimetic nanoparticles exhibited synergistic ferroptosis/immunotherapy against osteosarcoma.

Blocking the cytohesin-2/ARF1 axis by SecinH3 ameliorates osteoclast-induced bone loss via attenuating JNK-mediated IRE1 endoribonuclease activity.

cytohesin-2 is a guanine nucleotide exchange factor to activate ARF1 and ARF6, which are involved in various biological processes, including signal transduction, cell differentiation, cell structure organization, and survival. Nevertheless, there is a lack of evidence revealing the role of cytohesin-2 in osteoclast differentiation and in the development of osteoporosis. In this study, we find cytohesin-2 and ARF1 positively regulate osteoclast differentiation and function. Blocking the cytohesin-2 /ARF1 axis with SecinH3 or by genetic silencing of cytohesin-2 inhibits osteoclast formation and function in vitro. In vivo treatment with SecinH3 ameliorates ovariectomy-induced osteoporosis. Mechanistically, RNA-sequencing combined with molecular biological methodologies reveal that the regulatory function of cythohesin-2/ARF1 axis in osteoclast differentiation is mainly dependent on activating the JNK pathway. Further, in addition to the common viewpoint that JNK is activated by IRE1 via its kinase activity, we found that JNK can act upstream and regulate the endoribonuclease activity of IRE1 to promote XBP1 splicing. Both SecinH3 and silencing of cytohesin-2 inhibit JNK activation and IRE1 endoribonuclease activity, leading to the suppression of osteoclast differentiation. Taken together, our findings add new insights into the regulation between JNK and IRE1, and reveal that inhibiting the cytohesin-2/ARF1/JNK/IRE1 axis might represent a potential new strategy for the treatment of post-menopause osteoporosis.

Impact of Limb Salvage on Prognosis of Patients Diagnosed With Extremity Bone and Soft Tissue Sarcomas.

Background: Although clinicians and patients with extremity bone and soft tissue (EBST) are increasingly interested in limb salvage surgery (LSS), because of the minimal damage to physical appearance and function, however, there is still a lack of large-scale population studies on whether LSS improves the prognosis of patients. Purpose: The aim of this study was to compare the survival of patients with EBST sarcomas after receiving LSS and amputation. Methods: To conduct the population-based study, we identified 6,717 patients with a histologically diagnosed bone sarcoma and 24,378 patients with a histologically diagnosed soft tissue sarcoma from the Surveillance, Epidemiology, and End Results database. We analyzed overall survival (OS), cancer-specific survival (CSS), and non-sarcoma survival (NSS) using the Kaplan-Meier method, log-rank test or Gray test, Cox regression model, propensity score-matched analysis, and landmark analysis. Results: LSS could improve the prognosis in patients with most EBST subtypes, except for Ewing sarcomas and MPNST. However, in the subgroup without distant metastases, limb salvage increased CSS only for patients with osteosarcoma, Ewing sarcoma, and leiomyosarcoma, as well as NSS for patients with chondrosarcoma and synovial sarcoma. Landmark analysis further demonstrated that sarcoma survivors surviving <10 years could benefit from LSS but not for long-term survivors ≥10 years. Moreover, for patients with distant metastases, LSS could improve survival of osteosarcoma patients but worsen CSS among patients with MPNST. Landmark analysis further demonstrated that LSS improved survival among osteosarcomas patients with distant metastases only within 1 year after surgery. Moreover, patients receiving LSS and those receiving amputation had a high risk of dying from different non-sarcoma diseases during the postoperative follow-up. Conclusions: The impact of limb salvage on the prognosis of patients depends on the pathological subtype and stage of EBST sarcomas.

Global, Regional, and National Burden of Low Bone Mineral Density From 1990 to 2019: Results From the Global Burden of Disease Study 2019.

Objective: We aim to explore the global spatial prevalence and temporal trends of the burden of low bone mineral density (LBMD) worldwide, due to a lack of related studies. Design: Cross-sectional study. Methods: We used data from the Global Burden of Disease Study 2019 to conduct this study. LBMD in the GBD study includes both osteopenia and osteoporosis. The estimation for the prevalence, measured by the summary exposure value (SEV), and burden of LBMD was made in DisMod-MR 2.1, a Bayesian meta-regression tool. Correlation analysis was performed using the Spearman rank order correlation methods. The temporal trends were represented by the estimated annual percentage change (EAPC). Results: In 2019, there were 438 thousand deaths and 16.6 million DALYs attributable to LBMD, increasing by 111.1% and 93.8% respectively, compared to that in 1990. From 1990 to 2019, the prevalence of LBMD has decreased worldwide, but has increased in high-income North America. Some countries, such as the United States, Australia, Canada, and China had increased disability and mortality rates of LBMD with time. Countries with low socio-demographic index (SDI) had higher incidence and mortality rate than those with high SDI. The prevalence of LBMD was lower in males, but the attributable disability and mortality were higher in males in all years from 1990 to 2019. Conclusion: With population aging, countries worldwide, especially those with low-SDI, will face increasing challenges in reducing the burden attributable to LBMD and osteoporosis. The treatment of osteoporosis has been overlooked in men for a long time. Effective measures are warranted to control the prevalence and burden of LBMD.

Inhibition of MAT2A suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss.

Methionine adenosyltransferase II alpha (MAT2A) is the key enzyme to transform methionine and adenosine-triphosphate (ATP) to S-adenosylmethionine (SAM), a general methyl-group donor in vitro. MAT2A has been reported to participate in the NF-κB pathway and maintain the methylated modification, which also affects osteoclastogenesis. In this study, we found the expression of MAT2A was increased upon RANKL stimulation. Pharmacological inhibition of MAT2A by its selective inhibitor AG-270 or genetic silencing by MAT2A-shRNA suppressed osteoclast formation and function in vitro. In vivo treatment with the inhibitor AG-270 also prevented OVX-induced bone loss. Further study revealed that the inhibition of MAT2A affected osteoclast differentiation mainly by suppressing crucial transcription factors and reactive oxygen species induced by RANKL. A quasi-targeted metabolomics assay performed by LC-MS/MS indicated that SAM was reduced by MAT2A knockdown, and the administration of SAM partly rescued the effects of MAT2A inhibition on osteoclastogenesis. These findings revealed that MAT2A is crucial for osteoclastogenesis and might be a potential target for the treatment of osteoporosis attributed to osteoclast dysfunction.

Global incidence, prevalence, and disability of vertebral fractures: a systematic analysis of the global burden of disease study 2019.

BACKGROUND CONTEXT: In the context of the population growing and aging worldwide, the epidemiology, and burden of vertebral fracture have not been comprehensively analyzed. PURPOSE: To delineate the global number and rate of incidence, prevalence and burden of vertebral fracture in 2019, and the temporal trends from 1990 to 2019 by location, age, sex, and the socio-demographic index (SDI). STUDY DESIGN/SETTING: A cross-sectional study using data from the Global Burden of Disease Study 2019 (GBD study 2019). PATIENT SAMPLE: Patients with vertebral fracture documented in medical records or registrations and included in the GBD study 2019 from different countries worldwide. OUTCOME MEASURES: Age standardized incidence rate (ASIR), age standardized prevalence rate (ASPR), and age standardized years lived with disability (YLDs). METHODS: The GBD study 2019 was used to obtain data for this analysis. The incidence, prevalence and disability were analyzed by location, year, sex, age, and SDI. DisMod-MR 2.1, a Bayesian meta-regression tool, was used to produce the estimates for each value after adjustment for age, sex, and other variables. Estimated annual percentage change (EAPC) was calculated to represent the temporal trends from 1990 to 2019. Spearman's rank order correlation was used to determine the correlation between SDI and the incidence and burden of vertebral fracture. This work was supported by the Key Research and Development Program of Hubei Province of China (No. 2020BCB049), and no conflicts of interest-associated biases existed in this study. RESULTS: Globally, there were 8.6 million (95% uncertainty interval [UI], 6,6-11,3 million) incident cases, 5.3 million (95% UI, 4.6-6.2 million) prevalent cases, and 0.55 million (95% UI, 0.37-0.77 million) YLDs of vertebral fracture. Compared with 1990, the number of incident cases and YLDs in 2019 increased by 38% (95% UI, 23%-48%) and 75% (95% UI, 65%-85%), respectively, while the ASIR (EAPC, -0.28; 95% CI, -0.41 to -0.14), ASPR (EAPC, -0.12; 95% CI, -0.22 to -0.02) and age standardized YLD rate (ASYR) (EAPC, -0.13; 95% CI, -0.23 to -0.04) decreased during this period. High ASIR, ASPR and ASYR were commonly seen in high-SDI countries, such as high-income North America, Australia, Central and Eastern Europe. In the country level, positive correlations were observed between SDI and ASIR (rho, 0.596; p<.001) and ASYR (rho, 0.413; p<.001). Males had higher ASIR and ASYR worldwide in each year from 1990 to 2019. However, the incidence, and YLD rates in females surpassed that in males after 65 years of age. Increasing trends were observed for both incidence and YLD rates with age. Falls were the leading cause for vertebral fracture across all ages. CONCLUSIONS: The past thirty years have seen increasing numbers but decreasing rates of global incidence, prevalence, and disability of vertebral fractures, resulting from the growing population worldwide. With population aging, efforts are still in urgent need to address vertebral fracture related health outcomes.

Clinical and Radiological Outcomes of Two Modified Open-door Laminoplasties Based on a Novel Paraspinal Approach for Treatment of Multilevel Cervical Spondylotic Myelopathy.

STUDY DESIGN: A case-control study. OBJECTIVES: The aim of this study was to evaluate the outcomes of two modified laminoplasties (LPs) based on a novel paraspinal approach for treating multilevel cervical spondylotic myelopathy. SUMMARY OF BACKGROUND DATA: No laminoplasty through a natural intermuscular plane mimicking Wiltse approach to minimize intraoperative injury to extensor muscles has ever been developed and studied. METHODS: Ninety-two patients were enrolled, including patients treated with either modified LP and patients treated with concurrent conventional LP. Operation time, blood loss, and complications were recorded. Clinical outcomes were evaluated by VAS, JOA scores, and recovery rate. Cervical sagittal alignment was measured on cervical radiographs. Spinal canal expansion was assessed on CT scans. Cross-sectional area (CSA) and atrophy rate (AR) of cervical deep extensors were evaluated on MRI. RESULTS: The average follow-up duration was 33.05, 31.55, 33.02, and 32.52 months, respectively in each group. Compared to concurrent conventional procedure, unilateral muscle-preserving procedure displayed similar, whereas bilateral muscle-preserving procedure showed significantly increased operation time and blood loss; each modified procedure resulted in comparable and satisfied perioperative clinical scores, spinal canal expansion while achieving significantly lower axial pain incidence, better cervical lordosis maintenance, and better deep extensor preservation. AR of deep extensors on the open side was significantly lower than that on the hinge side. Bilateral paraspinal approach demonstrated significantly better muscle-preservation on the open side and increased operation duration, with similar clinical scores, axial pain incidence, cervical lordosis maintenance, and spinal canal expansion compared to unilateral paraspinal approach. Loss of cervical lordosis was strongly correlated with AR of deep extensors. CONCLUSION: Paraspinal approach is a good manner to protect deep extensor muscles; the two modified LPs have similar effects on clinical outcomes.Level of Evidence: 3.

A Competing Risk-based Prognostic Model to Predict Cancer-specific Death of Patients with Spinal and Pelvic Chondrosarcoma.

STUDY DESIGN: Retrospective analysis. OBJECTIVE: The aim of this study was to develop and validate a competing-risk-based prognostic model and a nomogram for predicting the three- and five-year probability of cancer-specific death (CSD) in patients with spinal and pelvic chondrosarcoma. SUMMARY OF BACKGROUND DATA: The issue of competing risk has rarely been addressed and discussed in survival analysis of bone sarcoma. In addition, the Fine and Gray model, a more accurate method for survival analysis in the context of competing risk, has also been less reported in prognostic study of chondrosarcoma. METHODS: A total of 623 patients with spinal or pelvic chondrosarcoma were identified from the SEER database and were divided into a training and a validation cohort. These two cohorts were used to develop and validate a prognostic model to predict the 3- and 5-year probability of CSD, considering non-CSD as competing risk. The C-index, calibration plot, and decision curve analysis were used to assess the predictive performance and clinical utility of the model. RESULTS: Older age (subdistribution hazards ratio [SHR]: 1.02, 95% confidence interval [CI]: 1.01∼1.03; P = 0.013), high grade (SHR: 2.68, 95% CI: 1.80∼3.99; P < 0.001), regional involvement (SHR: 1.66, 95% CI: 1.06∼2.58; P = 0.026), distant metastasis (SHR: 5.18, 95% CI: 3.11∼8.62; P < 0.001) and radical resection (SHR: 0.38, 95% CI: 0.24∼0.60; P < 0.001) were significantly associated with the incidence of CSD. These factors were used to build a competing-risk-based model and a nomogram to predict CSD. The C-index, calibration plot, and decision curve analysis indicated that the nomogram performs well in predicting CSD and is suitable for clinical use. CONCLUSION: A competing-risk based prognostic model is developed to predict the probability of CSD of patients with spinal and pelvic chondrosarcoma. This nomogram performs well and is suitable for clinical use.Level of Evidence: 4.

Inhibition of ACLY Leads to Suppression of Osteoclast Differentiation and Function Via Regulation of Histone Acetylation.

ATP-citrate lyase (ACLY), generating most of the nucleocytosolic acetyl coenzyme A (acetyl-CoA) for histone acetylation, links cell metabolism to epigenetic regulation. Recent investigations demonstrated that ACLY activated by metabolic reprogramming played an essential role in both M1 and M2 macrophage activation via histone acetylation. Previous studies also revealed that histone methylation and acetylation were critical for transcriptional regulation of osteoclast-specific genes. Considering that osteoclast differentiation also undergoes metabolic reprogramming and the activity of ACLY is always Akt-dependent, we inferred that receptor activator of NF-κB (RANK) activation might enhance the activity of ACLY through downstream pathways and ACLY might play a role in osteoclast formation. In the current study, we found that ACLY was gradually activated during RANK ligand (RANKL)-induced osteoclast differentiation from bone marrow-derived macrophages (BMMs). Both ACLY knock-down and small molecular ACLY inhibitor BMS-303141 significantly decreased nucleocytosolic acetyl-CoA in BMMs and osteoclasts and suppressed osteoclast formation in vitro. BMS-303141 also suppressed osteoclast formation in vivo and prevents ovariectomy (OVX)-induced bone loss. Further investigations showed that RANKL triggered ACLY translocation into nucleus, consistent with increasing histone H3 acetylation, which was correlated to ACLY. The H3 lysine residues influenced by ACLY were in accordance with GCN5 targets. Using GCN5 knock-down and overexpression, we showed that ACLY and GCN5 functioned in the same pathway for histone H3 acetylation. Analysis of pathways downstream of RANK activation revealed that ACLY was Akt-dependent and predominately affected Akt pathway. With the help of RNA-sequencing, we discovered Rac1 as a downstream regulator of ACLY, which was involved in shACLY-mediated suppression of osteoclast differentiation, cytoskeleton organization, and signal transduction and was transcriptionally regulated by ACLY via histone H3 acetylation. To summarize, our results proved that inhibition of ATP-citrate lyase led to suppression of osteoclast differentiation and function via regulation of histone acetylation. Rac1 could be a downstream regulator of ACLY. © 2021 American Society for Bone and Mineral Research (ASBMR).

Risk factors of regional lymph node (RLN) metastasis among patients with bone sarcoma and survival of patients with RLN-positive bone sarcoma.

BACKGROUND: Regional lymph node metastasis (RLNM) has been reported to be a prognostic factor for poor survival outcomes of bone sarcoma. However, studies about risk factors for RLNM of bone sarcoma are extremely rare, and the outcome of such patients remains to be explored. We aimed to identify risk factors for RLNM of bone sarcoma and conduct survival analysis for patients with bone sarcoma with RLNM. METHODS: A total of 10,641 patients confirmed of malignant bone sarcomas from 1983 to 2014 were identified from the Surveillance, Epidemiology, and End Results (SEER) database, with 311 being regional lymph node positive. Logistic regression analysis was used to identify risk factors for RLNM, while the Cox proportional hazards model and the Fine and Gray's regression model were used for survival analysis. RESULTS: The proportion of RLNM was 6.0% in Ewing sarcoma, 2.5% in osteosarcoma and 1.1% in chondrosarcoma. Other bone tumors together had a RLNM rate of 4.2%. Risk factors identified by the logistic regression analysis for RLNM were male patients, primary tumor site, tumor type and size. The multivariate Cox regression analysis suggested age, race, distant metastasis, tumor type and surgical treatment to be prognostic factors for the overall survival of patients with RLNM. Taking non-cancer-specific death as a competing risk, however, we found only age between 30-60 years [sub-distribution hazard ratio (SHR), 1.528, 95% CI, 1.028-2.271; P=0.02], distant metastasis (SHR, 2.418, 95% CI, 1.682-3.474; P<0.001) and surgery treatment (SHR, 0.493, 95% CI, 0.339-0.718; P<0.001) remained significant for the cancer-specific survival in the Fine and Gray's regression model. CONCLUSIONS: Predictive factors for RLNM of bone sarcoma are sex, tumor site, type and size. In the presence of RKNM, only age, distant metastasis and surgery treatment are prognostic factors for the outcome of patients with bone sarcoma.

Treatment of spinal cord compression caused by C2 osteochondroma with reconstruction and fusion after total resection: Case report and literature review.

Context: Osteochondroma is the most common benign tumor of the bone, but spinal osteochondroma is rare. We report a case of cervical osteochondroma in multiple exostoses arising from the lamina of the C2 vertebra, presenting with features of compressive myelopathy in a 22-year-old male. Total resection of the tumor and atlantoaxial fixation and fusion after reconstruction of the C1 posterior arch were performed.Findings: The patient recovered significantly. He was asymptomatic and no sign of recurrence was observed after one-year follow-up.Conclusions: Osteochondroma should be considered as a rare cause of spinal cord compression. Entire removal of the tumor will result in complete decompression and can reduce the risk of recurrence. We provide a new approach to reconstruct after resection.

Primary Tumor Resection Prolongs Survival in Spinal Chondrosarcoma Patients With Distant Metastasis.

STUDY DESIGN: Retrospective analysis. OBJECTIVE: To investigate (1) whether resection of primary tumor improves survival of metastatic spinal chondrosarcoma patients and (2) which subgroups of metastatic spinal chondrosarcoma patients benefit more from primary tumor resection. SUMMARY OF BACKGROUND DATA: Surgical resection is the mainstay of treatment for spinal chondrosarcoma, as chondrosarcoma is inherently resistant to radiotherapy and chemotherapy. However, evidence which justifies resection of the primary tumor for patients with metastatic spinal chondrosarcoma is still lacking. METHODS: We retrospectively included 110 patients with metastatic spinal chondrosarcoma in the Surveillance, Epidemiology, and End Results database from 1983 to 2016. The association between primary tumor resection and survival was evaluated using Kaplan-Meier analyses, log-rank tests, and multivariable Cox analyses. The effect of primary tumor resection on survival was further assessed in subgroups stratified by histologic subtype, tumor grade, and age. RESULTS: Overall, 110 patients were divided into surgery group (n = 55, 50%) and nonsurgery group (n = 55, 50%). Primary tumor resection was associated with both prolonged overall survival (hazard ratio 0.262, 95% confidence interval 0.149-0.462, P < 0.001) and cancer-specific survival (hazard ratio 0.228, 95% confidence interval 0.127-0.409, P < 0.001). When we focused on surgical effects in subgroups, primary tumor resection conferred survival advantage on patients with conventional subtype, grade I to III malignancy, and an age younger than 70 years old (P < 0.001 for overall and cancer-specific survival). However, primary tumor resection brought limited survival benefit for patients with dedifferentiated subtype and patients over 70 years old. CONCLUSION: The present population-based study for the first time reports a clear association between primary tumor resection and prolonged survival in metastatic spinal chondrosarcoma patients. Specifically, primary tumor resection was associated with improved survival in patients with conventional subtype, grade I to III malignancy, and an age younger than 70 years old. LEVEL OF EVIDENCE: 4.

Schisandrin B Inhibits Osteoclastogenesis and Protects Against Ovariectomy-Induced Bone Loss.

Osteoporosis is a systemic skeletal disease which is highly prevalent worldwide and considered to be associated with excessive bone resorption mediated by osteoclast. Osteoclast differentiation is featured by the activation of inflammation-related pathways and the generation of reactive oxygen species. Schisandrin B is a bioactive compound with strong antiinflammation and antioxidative properties, we thus speculated that Schisandrin B might serve as a potential candidate for osteoporosis. In the present study, we found that the formation and` function of osteoclasts were dramatically suppressed by Schisandrin B. And consistent with the in vitro results, treatment with Schisandrin B attenuated ovariectomy-induced bone loss in mice. Moreover, Schisandrin B notably inhibited the activation of mitogen activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways and scavenged ROS by activating nuclear factor E2 p45-related factor 2 (Nrf2) signaling. In conclusion, our study indicates that Schisandrin B is an effective approach to treat osteoporosis and other osteoclast-related diseases.

Conditional Survival Analysis for Spinal Chondrosarcoma Patients After Surgical Resection.

STUDY DESIGN: Retrospective analysis. OBJECTIVE: To evaluate conditional survival after surgical resection for spinal chondrosarcoma patients. SUMMARY OF BACKGROUND DATA: Survival estimates are usually reported as survival from the time of surgery, but survival probabilities can change over time. Conditional survival, which is a measure of prognosis for patients who have survived a defined period of time, may be more clinically precise and relevant. However, data on conditional survival for spinal chondrosarcoma patients after surgical resection are still lacking. METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify 436 spinal chondrosarcoma patients who underwent surgical resection from 1994 and 2013. Kaplan-Meier analyses and Cox regression modeling were performed to evaluate prognostic factors associated with overall survival. Five-year conditional survival (i.e., probability of surviving an additional 5 years, given that a patient has already survived x years) was calculated as 5-CS(x) = OS(x+5)/OS(x). The effect of prognostic factors on conditional survival was also explored. RESULTS: Four hundred thirty six patients were included in the study cohort. Overall, 1-, 3-, and 5-year overall survival were 92.8%, 79.1%, and 70.3%, respectively. Five-year conditional survival at 1, 3, and 5 years after surgery were 72.9%, 79.0%, and 87.5%. The overall survival rates were lower in cases of age more than or equal to 60 years, male patient, dedifferentiated subtype, Grade III tumor, tumor size more than or equal to 10 cm, distant metastasis, and radiotherapy. Conditional survival improved over time in each subgroup divided by age, sex, race, year of diagnosis, grade, tumor size, extent of disease (EOD), and radiotherapy. In addition, patients with the least favorable prognosis at baseline experienced the greatest increase in 5-year conditional survival over time (e.g., Grade I/II: 78.0%-89.7%, Δ11.7% vs. Grade III: 36.5%-66.6%, Δ30.1%; Localized/Regional: 72.9%-88.1%, Δ15.2% vs. Distant: 43.5%-74.1%, Δ30.6%). CONCLUSION: Conditional survival for spinal chondrosarcoma patients after surgical resection improves over time, especially for patients with initial high-risk characteristics. Information derived from conditional survival analysis may provide individualized approaches to surveillance and treatment of spinal chondrosarcoma. LEVEL OF EVIDENCE: 4.

The Effect of Footprint Mismatch on Heterotopic Ossification After Cervical Disk Replacement.

STUDY DESIGN: This was a retrospective study. OBJECTIVE: The objective of this study was to analyze risk factors of heterotopic ossification (HO) after cervical disk replacement (CDR) and evaluate the effect of footprint mismatch on HO. SUMMARY OF BACKGROUND DATA: Incidence of HO after CDR is high, but the exact related factors have not been fully elucidated. MATERIALS AND METHODS: Radiographic data of patients who had undergone CDR with Prestige LP or Discover prosthesis in Tongji Hospital from July 2012 to December 2015 were reviewed. HO was graded according to McAfee classification and classified according to Jin morphologic classification. Footprint matching degree was evaluated using 3-dimensional computed tomographic images. Cervical sagittal alignment, functional spinal unit height, and range of motion were measured on radiographs. Preexisting degeneration was scored using Walraevens scoring system. Postulated risk factors including general factors, cervical sagittal alignment, functional spinal unit height, range of motion, postoperative biomechanical changes, preexisting degeneration, number of surgical levels, prosthesis type, use of nonsteroid anti-inflammatory drugs, and footprint matching degree were analyzed by first univariate tests, and then multivariate logistic regression was done to examine the relation with HO occurrence. Effect of footprint mismatch on type 1 HO of morphologic classification was evaluated. RESULTS: Data of 46 patients were collected; 43 were finally evaluated with a total 57 prostheses implanted, with a mean follow-up duration of 41.16±12.49 months. No significant differences in basic characteristics existed between 2 prosthesis groups, except follow-up time. Incidence of HO was 66.7%. Mean footprint matching degree in sagittal plane was 0.877±0.068 and in coronal plane was 0.852±0.092. Mean overall footprint matching degree was 0.699±0.102 (range: 0.388-0.993). Prosthesis type and footprint matching degree were significantly related with HO among all postulated risk factors in both univariate and multivariate analyses (P<0.05); the latter had larger Exp(B). Type 1 HO occurrence significantly related with footprint mismatch. CONCLUSIONS: Incidence of HO after CDR was high, and serious footprint mismatch existed. HO occurrence was significantly related with prosthesis type and footprint matching degree; the latter played a more important role.

Inhibition of PFKFB3 suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss.

Osteoclasts are multinucleated cells derived from the monocyte/macrophage cell lineage under the regulation of receptor activator of nuclear factor-κB ligand (RANKL). In previous studies, stimulation by RANKL during osteoclastogenesis was shown to induce a metabolic switch to enhanced glycolytic metabolism. Thus, we hypothesized that blockage of glycolysis might serve as a novel strategy to treat osteoclast-related diseases. In the present study, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), an essential regulator of glycolysis, was up-regulated during osteoclast differentiation. Genetic and pharmacological inhibition of PFKFB3 in bone marrow-derived macrophages suppressed the differentiation and function of osteoclasts. Moreover, intraperitoneal administration of the PFKFB3 inhibitor PFK15 prevented ovariectomy-induced bone loss. In addition, glycolytic activity characterized by lactate accumulation and glucose consumption in growth medium was reduced by PFKFB3 inhibition. Further investigation indicated that the administration of L-lactate partially reversed the repression of osteoclastogenesis caused by PFKFB3 inhibition and abrogated the inhibitory effect of PFK15 on the activation of NF-κB and MAPK pathways. In conclusion, the results of this study suggest that blockage of glycolysis by targeting PFKFB3 represents a potential therapeutic strategy for osteoclast-related disorders.

Serum- and Glucocorticoid-inducible Kinase 1 is Essential for Osteoclastogenesis and Promotes Breast Cancer Bone Metastasis.

Bone metastasis is a severe complication associated with various carcinomas. It causes debilitating pain and pathologic fractures and dramatically impairs patients' quality of life. Drugs aimed at osteoclast formation significantly reduce the incidence of skeletal complications and are currently the standard treatment for patients with bone metastases. Here, we reported that serum- and glucocorticoid-inducible kinase 1 (SGK1) plays a pivotal role in the formation and function of osteoclasts by regulating the Ca2+ release-activated Ca2+ channel Orai1. We showed that SGK1 inhibition represses osteoclastogenesis in vitro and prevents bone loss in vivo Furthermore, we validated the effect of SGK1 on bone metastasis by using an intracardiac injection model in mice. Inhibition of SGK1 resulted in a significant reduction in bone metastasis. Subsequently, the Oncomine and the OncoLnc database were employed to verify the differential expression and the association with clinical outcome of SGK1 gene in patients with breast cancer. Our data mechanistically demonstrated the regulation of the SGK1 in the process of osteoclastogenesis and revealed SGK1 as a valuable target for curing bone metastasis diseases.

Myoferlin, a Membrane Protein with Emerging Oncogenic Roles.

Myoferlin (MYOF), initially identified in muscle cells, is a member of the Ferlin family involved in membrane fusion, membrane repair, and membrane trafficking. Dysfunction of this protein is associated with muscular dysfunction. Recently, a growing body of studies have identified MYOF as an oncogenic protein. It is overexpressed in a variety of human cancers and promotes tumorigenesis, tumor cell motility, proliferation, migration, epithelial to mesenchymal transition, angiogenesis as well as metastasis. Clinically, MYOF overexpression is associated with poor outcome in various cancers. It can serve as a prognostic marker of human malignant disease. MYOF drives the progression of cancer in various processes, including surface receptor transportation, endocytosis, exocytosis, intercellular communication, fit mitochondrial structure maintenance and cell metabolism. Depletion of MYOF demonstrates significant antitumor effects both in vitro and in vivo, suggesting that targeting MYOF may produce promising clinical benefits in the treatment of malignant disease. In the present article, we reviewed the physiological function of MYOF as well as its role in cancer, thus providing a general understanding for further exploration of this protein.