CHRDL2 activates the PI3K/AKT pathway to ameliorate glucocorticoid-induced damages to bone microvascular endothelial cells (BMECs).

Steroid-induced avascular necrosis of the femoral head (ANFH) is characterized by the death of bone tissues, leading to the impairment of normal reparative processes within micro-fractures in the femoral head. Glucocorticoid (GCs)-induced bone microvascular endothelial cell (BMEC) damage has been reported to contribute to ANFH development. In this study, differentially expressed genes (DEGs) between necrosis of the femoral head (NFH) and normal samples were analyzed based on two sets of online expression profiles, GSE74089 and GSE26316. Chordin-like 2 (CHRDL2) was found to be dramatically downregulated in NFH samples. In GCs-stimulated BMECs, cellular damages were observed alongside CHRDL2 down-regulation. GCs-caused cell viability suppression, cell apoptosis promotion, tubule formation suppression, and cell migration suppression were partially abolished by CHRDL2 overexpression but amplified by CHRDL2 knockdown; consistent trends were observed in GCs-caused alterations in the protein levels of VEGFA, VEGFR2, and BMP-9 levels, and the ratios of Bax/Bcl-2 and cleaved-caspase3/Caspase3. GC stimulation significantly inhibited PI3K and Akt phosphorylation in BMECs, whereas the inhibitor effects of GCs on PI3K and Akt phosphorylation were partially attenuated by CHRDL2 overexpression but further amplified by CHRDL2 knockdown. Moreover, CHRDL2 overexpression caused improvement in GCs-induced damages to BMECs that were partially eliminated by PI3K inhibitor LY294002. In conclusion, CHRDL2 is down-regulated in NFH samples and GCs-stimulated BMECs. CHRDL2 overexpression could improve GCs-caused BMEC apoptosis and dysfunctions, possibly via the PI3K/Akt pathway.

Both Acetabular and Femoral Reconstructions With Impaction Bone Grafting in Revision Total Hip Arthroplasty: Case Series and Literature Review.

Background: Extensive bone loss on femur and acetabulum posed a big challenge to orthopedists in total hip revision surgeries. Impaction bone grafting (IBG) as a valuable bone preservation technique could effectively address this problem. Either IBG revision on the femoral or acetabular side was well studied, while its use on both sides in one operation was not. The aim of this study is to present the outcomes of IBG on both femoral and acetabular sides at first-time hip revision. Methods: We retrospectively reviewed 8 patients (mean follow-up of 5.8 years) undergoing first-time revision with IBG on both acetabular and femoral sides at our institution. The Paprosky classification system was used to classify bone defects. Freeze-dried allografts and cemented prostheses were used in all patients. Postoperative complications and rerevision rates were reported. Results: Five patients presented a Paprosky type IIC acetabular defect, 3 with a type IIIB, IIIA, and IIC defect, respectively. Three patients presented with a type IV femoral defect, 3 with a type IIIB defect, and 2 with a type II defect. Two patients developed complications, while one had an intraoperative femoral fracture and one had delayed wound healing. At the latest follow-up, no patient had rerevisions or operations related to the prosthesis. Conclusions: IBG in combination with cemented prosthesis is a profitable biological reconstruction revision technique that could provide satisfying midterm outcomes. We first propose the use of blood clots mixed with bone grafts for potential bone incorporation enhancement, while its specific effects need to be verified in further studies.

GATA4-activated lncRNA MALAT1 promotes osteogenic differentiation through inhibiting NEDD4-mediated RUNX1 degradation.

Postmenopausal osteoporosis (PMOP) brings a lot of inconvenience to patients and serious economic burden to society. The osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) plays vital role in the process of PMOP treatment. However, the functional mechanism remains unclear. In this study, GATA4, MALAT1 and KHSRP were downregulated in bone tissues of PMOP patients, while NEDD4 was overexpressed. Through functional experiments, GATA4 overexpression strikingly accelerated osteogenic differentiation of BMSCs and promoted bone formation in vitro and in vivo, while these effects were dramatically reversed after MALAT1 silence. Intermolecular interaction experiments confirmed that GATA4 activated the transcription of MALAT1, which could form a 'RNA-protein' complex with KHSRP to decay NEDD4 mRNA. NEDD4 promoted the degradation of Runx1 by ubiquitination. Moreover, NEDD4 silencing blocked the inhibitory effects of MALAT1 knockdown on BMSCs osteogenic differentiation. In sum up, GATA4-activated MALAT1 promoted BMSCs osteogenic differentiation via regulating KHSPR/NEDD4 axis-regulated RUNX1 degradation, ultimately improving PMOP.

miR-122-5p targets GREM2 to protect against glucocorticoid-induced endothelial damage through the BMP signaling pathway.

Glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH) accounts for a big portion of non-traumatic ONFH; nevertheless, the pathogenesis has not yet been fully understood. GC-induced endothelial dysfunction might be a major contributor to ONFH progression. The Gene Expression Omnibus (GEO) dataset was analyzed to identify deregulated miRNAs in ONFH; among deregulated miRNAs, the physiological functions of miR-122-5p on ONFH and endothelial dysfunction remain unclear. In the present study, miR-122-5p showed to be under-expressed within GC-induced ONFH femoral head tissues and GC-stimulated bone microvascular endothelial cells (BMECs). In human umbilical vein endothelial cells (HUVECs) and BMECs, GC stimulation significantly repressed cell viability, promoted cell apoptosis and increased the mRNA expression of proinflammatory cytokines, such as TNF-α, IL-1ß, and IFN-γ. After overexpressing miR-122-5p, GC-induced endothelial injuries were attenuated, as manifested by rescued cell viability, cell migration, and tube formation capacity. Regarding the BMP signaling, GC decreased the protein levels of BMP-2/6/7 and SMAD-1/5/8, whereas miR-122-5p overexpression significantly attenuated the inhibitory effects of GC on these proteins. Online tool and experimental analyses revealed the direct binding between miR-122-5p and GREM2, a specific antagonist of BMP-2. In contrast to miR-122-5p overexpression, GREM2 overexpression aggravated GC-induced endothelial injury; GREM2 silencing partially eliminated the effects of miR-122-5p inhibition on GC-stimulated HUVECs and BMECs. Finally, GREM2 silencing reversed the suppressive effects of GC on BMP-2/6/7 and SMAD-1/5/8, and attenuated the effects of miR-122-5p inhibition on these proteins upon GC stimulation. Conclusively, the present study demonstrates a miR-122-5p/GREM2 axis modulating the GC-induced endothelial damage via the BMP/SMAD signaling. Considering the critical role of endothelial function in ONFH pathogenesis, the in vivo role and clinical application of the miR-122-5p/GREM2 axis is worthy of further investigation.

Is Lutikizumab, an Anti-Interleukin-1α/ß Dual Variable Domain Immunoglobulin, efficacious for Osteoarthritis? Results from a bayesian network meta-analysis.

OBJECTIVE: Most guidelines recommend the use of nonsteroidal anti-inflammatory drugs (NSAIDs), duloxetine, and tramadol for the nonoperative treatment of osteoarthritis (OA), but the use of them is limited by the tolerability and safety concerns. Lutikizumab is a novel anti-IL-1α/ß dual variable domain immunoglobulin that can simultaneously bind and inhibit IL-1α and IL-1ß to relieve the pain and dysfunction symptoms. We conducted this network meta-analysis to comprehensively compare the clinical efficacy and safety of lutikizumab with other drugs recommended by guidelines. METHODS: We conducted a Bayesian network and conventional meta-analyses to compare the efficacy and safety of lutikizumab with other traditional drugs. All eligible randomized clinical trials, in PubMed, CNKI, EMBASE, and Web of Science databases, from January 2000 to January 2020, were included. The Cochrane risk of the bias assessment tool was used for quality assessment. Pain relief, function improvement, and risk of adverse effects (AEs) were compared in this study. RESULTS: 24 articles with 11858 patients were included. Duloxetine (DUL) had the largest effect for pain relief (4.76, 95% CI [2.35 to 7.17]), and selective cox-2 inhibitors (SCI) were the most efficacious treatment for physical function improvement (SMD 3.94, 95% CI [2.48 to 5.40]). Lutikizumab showed no benefit compared with placebo for both pain relief (SMD 1.11, 95% CI [-2.29 to 4.52]) and function improvement (SMD 0.992, 95% CI [-0.433 to 4.25]). Lutikizumab and all other drugs are of favorable tolerance for patients in the treatment of OA compared with placebo. CONCLUSIONS: Lutikizumab, the new anti-Interleukin-1α/ß dual variable domain immunoglobulin, showed no improvement in pain or function when compared with placebo. Selective cox-2 inhibitors and duloxetine remain the most effective and safest treatment for OA. More high-quality trials are still needed to reconfirm the findings of this study.

Tumor ablation using novel photothermal NaxWO3 nanoparticles against breast cancer osteolytic bone metastasis.

BACKGROUNDS: Profiting from the development of nanomaterials, photothermal therapy (PTT) has been discovered as efficient tumor ablation strategy for breast cancer. MATERIALS AND METHODS: Novel oxygen vacancy-rich tungsten bronze nanoparticles (NaxWO3) were synthesized through a simple pyrogenic decomposition process. TEM, XRD, UV-vis-NIR, photothermal conversion ability, and photothermal stability were performed. The viabilities of 293T and 4T1 cells after treating with 200 µg/mL NaxWO3 nanoparticles for 24 or 48 hrs were both above 80%, which proved the good biosafety and cytotoxicity of NaxWO3 in vitro. Two in vivo breast cancer models, namely percutaneous and intratibial 4T1 models were established and NaxWO3 (20 mg/kg) with power intensity of 1.5 W/cm2 980 nm laser photothermal treatment was used in vivo. RESULTS: We successfully synthesized ~150 nm NaxWO3 nanoparticles with desirable PTT effects, as evidenced by the temperature increase from 25.8°C to 41.8°C in 5 mins under the irradiation of 980 nm laser (1 mg/mL). Also, cellular compatibility of NaxWO3 nanoparticles was found upon physiologic 293T cells, in contrast with significant cytotoxicity against breast cancer 4T1 cell in vitro dose-dependently. Besides, two in vivo breast cancer models showed the decent tumor ablation ability of NaxWO3 nanoparticles, demonstrating percutaneous 4T1 tumor elimination without recurrence during 2 weeks observation as well as intratibial breast cancer inhibition with decreased bone destruction and tumor volume after NaxWO3+PTT in vivo. CONCLUSION: For the first time, we developed a novel oxygen vacancy-rich tungsten bronze nanoparticles (NaxWO3) through a simple pyrogenic decomposition process for PTT. Both in vitro and in vivo experiments showed the good PTT ability and tumor ablation effects of synthesized NaxWO3 nanoparticles against breast cancer osteolytic bone metastasis. Additionally, our oxygen-deficient NaxWO3 nanoparticles will expand the research horizons of PTT nanomaterials.

Partial Component-Retained 2-Stage Reconstruction in the Treatment of Infected Hip Arthroplasty.

BACKGROUND: It is considered the gold standard treatment for infected hip arthroplasty to remove and reimplant the corresponding whole set of implant components before and after infection control, but it usually causes substantial bone loss to remove the well-fixed cup or stem, which may increase the difficulty in reconstruction. We would like to determine whether infected hip arthroplasty can be treated without removal of a well-fixed cup or stem. METHODS: Patients with infected hip arthroplasty and a radiographically well-fixed, cementless cup or stem were selected. During the first surgical stage, we retained the stem or cup if these cannot be removed using a stem or cup extractor. We performed the reimplantation surgery after control of infection. RESULTS: From January 2008 to December 2016, 26 patients underwent partial component-retained 2-stage reconstruction. All the patients were free of infection with a mean follow-up time of 43.85 months. CONCLUSION: Partial component-retained 2-stage reconstruction may be a treatment option for infected total hip arthroplasty with a well-fixed component in patients.

Bioinformatics analysis of differentially expressed genes involved in human developmental chondrogenesis.

Osteoarthritis (OA), also known as degenerative arthritis, affects millions of people all over the world. OA occurs when the cartilage wears down over time, which is a worldwide complaint. The aim of this study was to screen and verify hub genes involved in developmental chondrogenesis as well as to explore potential molecular mechanisms.The expression profiles of GSE51812 were downloaded from the Gene Expression Omnibus (GEO) database, which contained 9 samples, including 6-week pre-chondrocytes (PC, 6 independent specimens) and 17-week fetal periarticular resting chondrocytes (RC, 3 independent specimens). The raw data were integrated to obtain differentially expressed genes (DEGs) and were further analyzed with bioinformatics analysis. The Gene Ontology (GO) and pathway enrichment of DEGs were conducted via Database for Annotation, Visualization, and Integrated Discovery (DAVID). The protein-protein interaction (PPI) networks of the DEGs were constructed based on data from the search tool for the retrieval of interacting genes (STRING) database. An intersection figure was provided to show the relationship between the DEGs identified in this study and genes from any existed related studies.A total of 9486 DEGs, including 4821 upregulated genes and 4665 downregulated genes were observed. The top 30 developmental chondrogenesis associated genes were identified, including matrix metalloproteinase (MMP)1, MMP3, MMP13, prostaglandin-endoperoxide synthase 2 (PTGS2), and so on. The majority of DEGs, including PTGS2, CCL20, CHI3L1, LIF, CXCL8, and CXCL12 were intensively enriched in immune-associated biological process terms, including inflammatory, and immune responses. Additionally, the majority of DEGs were mainly enriched in NF-kappa ß (NF-kß) signaling pathway and tumor necrosis factor (TNF) signaling pathway. The hub genes identified in STRING and Cytoscape databases included MMP1, MMP3, MMP13, PTGS2 and so on. Among the top 30 upregulated and downregulated DEGs, there were 15 genes have been reported to be associated with OA or developmental chondrogenesis.This large scale gene expression study observed genes associated with human developmental chondrogenesis and their relative GO function, which may offer opportunities for the research for cartilage tissue engineering and novel insights into the prevention of OA in the near future.

Acquired heterotopic ossification in hips and knees following encephalitis: case report and literature review.

BACKGROUND: Heterotopic ossification (HO) is a rare and potentially detrimental complication of soft-tissue trauma, amputations, central nervous system injury (traumatic brain injuries, spinal cord lesions, tumors, encephalitis), vasculopathies, arthroplasties and burn injury, characterized by lamellar bone growth in non-osseous tissues such as the muscle and the joint capsule. Heterotopic ossification associated with encephalitis is rare and the occurrence of excessive, symptomatic heterotopic ossification around bilateral hips and bilateral knees is rarely described in the literature. CASE PRESENTATION: We present a 47-year-old man with heterotopic ossification in the bilateral hips and bilateral knees that prevented him from walking after being attacked by encephalitis as the case study. He developed severe pain and significantly impaired range of motion of bilateral hips and bilateral knees. Research so far revealed that the management of heterotopic ossification is controversial. After requiring revision surgery resection of heterotopic ossification, reconstruction of the medial collateral ligament and adjunctive pharmacotherapy of 200 mg Celecoxib for 8 weeks after operation, he regained mobility of his joints. On review of X-ray, there was no recurrence of HO and no loosening of rivets which were used in the reconstruction of medial collateral ligament. CONCLUSION: Heterotopic ossification in the bilateral hip joints and bilateral knee joints associated with encephalitis have never been reported previously. Daily functions of heterotopic ossification patients can be hampered by pain, inflammation, reduced mobility, the loss of normal posture and other complications. Further studies of presumptive root causes, the early diagnosis, preventability and optimal therapeutic measures for heterotopic ossification following encephalitis are required. Different patient should be managed with different appropriated protocol based on the risk of individual patient and the institutional experience.

[Treatment of external fixator in young patients with valgus deformity of the knee companied with leg shortening].

OBJECTIVE: To explore the efficacy and experience of callus distraction technique with the external fixator for valgus deformity of the knee companied with leg shortening in young patients and to provide evidence for selecting reasonable therapy. METHODS: From January 2002 to January 2009, the clinical data of 28 young patients (17 males and 11 females, aged 8 to 14, mean age 11.9 years) treated with callus distraction, who had valgus deformity of the knee, companied with leg shortening, were analyzed retrospectively. Three had bilateral total valgus deformity of the knee, with a total of 31 knees. Before the operation, the abnormal limbs shortened from 3 to 7 cm (average 4.1 cm) companied with the normal one. The tibiofemoral angle ranged from 138° to 160° (mean angle 148°) and the Condyle interval from 5 to 33 cm (mean interval 15.2 cm). RESULTS: The 28 patients were followed up for 35 to 84 ( mean 62 ) months. The extent length ranged from 4.5 to 10.1 cm (average 6.8 cm). The tibiofemoral angle ranged from 169° to 175° (mean 173°) after the union. The patients resumed the normal length of limbs, and the severe valgus deformity of the knee was corrected. CONCLUSION: Callus distraction with external fixator is effective for serious valgus deformity of the knee companied with leg shortening.