Ankylosing spondylitis (AS) is an autoimmune disease characterized by fibroblasts ossification. However, effective drug therapy for AS is lacking. As an antidiabetic drug, metformin has demonstrated an antiosteogenic effect on osteoblasts in vitro. And it is also a kind of specific agonists for adenosine 5′-monophosphate activated protein kinase (AMPK), which is blocked in the process of AS. Given the role in antiosteogenesis and AMPK activating, metformin was investigated of its effect on fibroblasts harvested from capsular ligament of patients with femoral neck fracture and AS. Osteogenic specific makers (Alp, Bglap, Runx2, Bmp2, and Col1) in fibroblasts administered with metformin (20 μg/mL) were detected by ALP staining, alizarin red staining, qPCR, and Western blotting after 7 and 14 days of culture. Inflammation genes (il1-β and il6) and pathway (Pi3k, Akt, and Ampk) associated markers were also evaluated. Our results showed that osteogenic specific markers were greatly downregulated and ossification was effectively inhibited in AS fibroblasts after addition of metformin. Levels of inflammation markers were also decreased by metformin. Thus, metformin exerts potent effect on suppression of ossification and inflammation in AS fibroblasts via the activation of Pi3k/Akt and AMPK pathways, which may be developed as a potential agent for treatment of AS. K E Y W O R D Sankylosing spondylitis, fibroblasts, metformin, ossification Xiong Qin, Tongmeng Jiang, and Sijia Liu contributed equally to this work.

PurposeBy examining and identifying circulating tumor cell (CTC) counts and subtypes of peripheral blood in osteosarcoma patients, we evaluated the relationship between CTCs and characteristics of osteosarcoma patients, as well as CTC changes after neoadjuvant chemotherapy and surgery.MethodsCanPatrol™ CTC technology was used to detect CTCs in peripheral blood before and after treatment in 32 osteosarcoma patients. Peripheral blood samples from 10 healthy volunteers were included as controls and examined for the presence of CTCs.ResultsOf the 32 osteosarcoma patients, CTCs were detected in 30 patients before treatment, and the average CTC count was 14.06±9.08. No CTCs were detected in the 10 healthy volunteers. The detected CTCs were divided into epithelial CTCs, mesenchymal CTCs (M-CTCs), and biophenotypic epithelial/mesenchymal CTCs. The average number of pretreatment CTCs was higher in stage III patients than in stage IIB patients (P=0.012). Twenty-eight patients were screened for changes in CTC count at 1 week after neoadjuvant chemotherapy and at 4 weeks after surgery. We divided these 28 patients into two groups according to the changes in the percentage of M-CTCs before and after treatment, and the results showed that the disease-free survival (DFS) was significantly shorter in the M-CTC percentage-increased group than in the M-CTC percentage-decreased or no-change group (P=0.032). Five patients with stage II osteosarcoma were examined for CTCs at the appearance of lung metastases, and the total number of CTCs was found to be higher at the appearance of lung metastases than before treatment in these patients.ConclusionThe rate of presence of CTCs in the peripheral blood of osteosarcoma patients is high, and patients with an increased percentage of M-CTCs after treatment have a shorter DFS. The dynamic monitoring of changes in CTC counts after treatment has clinical significance for the timely detection of recurrence or metastasis.

Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized with heterotopic ossification of the axis joints ligaments, resulting in joint disability. MicroRNAs (miRNAs) are regulators of mRNAs that play a crucial role in the AS pathological process. Here, we showed that the level of miR-17-5p was significantly higher in fibroblasts and ligament tissues from AS patients as compared to the non-AS individuals. Knockdown of the miR-17-5p from the fibroblasts derived from AS patients exhibited decreased osteogenic differentiation and ossification. On the other hand, AS patient-derived fibroblasts overexpressing miR-17-5p displayed the increased osteogenesis. Furthermore, inhibition of miR-17-5p ameliorated osteophyte formation, and the sacroiliitis phenotype in AS rats received emulsified collagen. Mechanistically, miR-17-5p regulated osteogenic differentiation by targeting the 3ʹ UTR of ankylosis protein homolog (ANKH). Also, downregulation of miR-17-5p slowed AS progression through regulation of cytokines, such as dickkopf-1 (DKK1) and vascular endothelial growth factor (VEGF). In conclusion, our findings reveal a role of the miR-17-5p-ANKH axis in the regulation of heterotopic ossification, which is essential for therapeutic intervention in heterotopic ossification in AS.

PurposeWe aimed to conduct a meta-analysis of published cohort studies to evaluate the risk of hip fracture in patients undergoing dialysis or kidney transplantation (KT).MethodsWe identified relevant studies by searching PubMed, EMBASE and Google Scholar databases from their inception to December 31, 2017. Cohort studies evaluating risk of hip fractures in patients undergoing dialysis or KT were considered included. The methodological quality of the cohort studies was assessed using the modified Newcastle-Ottawa scale.ResultsIn our meta-analysis of 14 retrospective cohort studies, a total of more than 1.5 million patients undergoing dialysis or KT were included, of whom more than 30,000 had hip fractures. After the merger, the proportion of hip fractures was 1.92% (95% CI, 1.38%−2.46%) with significant heterogeneity (I2=99.9%, P=0.000) in all patients, and the incidence rate of hip fractures (per 1,000 person-years) was 8.95 (95% CI, 4.05–13.85) with significant heterogeneity (I2=99.9%, P=0.000). The pooled relative risks (RR) value for dialysis patients compared with the general population were 6.35 (95% CI, 4.53–8.88) for male and 5.57 (95% CI, 4.44–6.99) for female. The pooled RR value for hemodialysis (HD) patients compared with peritoneal dialysis (PD) patients was 1.39 (95% CI, 1.13–1.70) with no heterogeneity (I2=0.0%, P=0.763).ConclusionIn conclusion, the present meta-analysis reveals that about 2% of dialysis or KT patients go on to sustain a hip fracture during follow-up, with the overall hip fracture incidence rates being 8.95 per 1,000 person-years. The overall risk of hip fracture was more than 5-fold higher in dialysis patients than in the general population. Among patients on PD, HD, and KT, HD and KT patients had the highest and the lowest risk of hip fractures, respectively.