The Role and Potential Mechanism of Complement Factor D in Fibromyalgia Development.

Purpose: Fibromyalgia (FM) is a syndrome characterized by chronic musculoskeletal pain. Its clinical symptoms include both somatic and psychiatric symptoms, making the treatment of FM extremely challenging. The cause of FM is still unknown, and some patients do not improve their symptoms even after long-term active treatment. Thus, the development of new targeted therapies is important to reduce pain and improve quality of life for FM patients. Methods: In this study, we screened genes and secreted factors that play key roles in FM through bioinformatics and big data analysis. Furthermore, we performed CCK-8, qRT-PCR, glucose, ATP and lactate content testing, dual luciferase reporter gene assay to investigate the potential mechanism of complement factor D in fibromyalgia development. Results: In bioinformatics and big data analysis, we identified CFD was negatively correlated with the pro-inflammatory factor IL-6 and positively correlated with the anti-inflammatory factor IL-4, which suggested that CFD may be an anti-inflammatory factor. Through cellular assays, we verified that CFD reversed the decrease in IL-4 expression and the increase in IL-6 expression in BV2 cells caused by ATP. Conclusion: In summary, based on bioinformatic methods and big data mining we obtained a new target CFD for FM, and further experiments verified that CFD has significant inhibition of ATP-induced neuropathic pain. These findings provide a new theoretical basis for the clinical translation of CFD.

MAKO robot-assisted total knee arthroplasty cannot reduce the aggravation of ankle varus incongruence after genu varus correction ≥ 10°: a radiographic assessment.

INTRODUCTION: The objective of this study was to investigate the ankle alignment alterations after the correction of knee varus deformity in MAKO robot-assisted total knee arthroplasty (MA-TKA). METHODS: A retrospective analysis was conducted for 108 patients with TKA from February 2021 to February 2022. Patients were divided into two groups based on MAKO robot involvement during the procedure: the MA-TKA group (n = 36) and the conventional manual total knee arthroplasty (CM-TKA) group (n = 72). The patients were divided into four subgroups according to the degree of surgical correction of the knee varus deformity. Seven radiological measurements were evaluated pre and post-surgery: mechanical tibiofemoral angle (mTFA), mechanical lateral distal femoral angle (mLDFA), medial proximal tibial angle (MPTA), lateral distal tibial angle (LDTA), tibial plafond inclination angle (TPIA), talar inclination angle (TIA), and tibiotalar tilt angle (TTTA). TTTA is a quantitative representation of the extent of ankle incongruence. RESULTS: The number of mTFA, mLDFA, and MPTA outliers in the MA-TKA group was significantly lower compared to the CM-TKA group (P<0.05). Knee varus deformity was properly corrected and the mechanical axis was restored in all patients, regardless of the treatment group. Only for varus corrections ≥ 10° did TTTA change significantly (p < 0.01) and ankle varus incongruence aggravate post-operation. The ΔTTTA correlated negatively with ΔTFA (r=-0.310,P = 0.001) and correlated positively with ΔTPIA (r = 0.490,P = 0.000). When the varus correction was ≥ 7.55°, the probability of ankle varus incongruence exacerbation increased 4.86-fold. CONCLUSION: Compared with CM-TKA, MA-TKA osteotomy showed more precision but was unable to reduce post-operation ankle varus incongruence. When the varus correction ≥ 10°, ankle varus incongruence aggravated, while when the varus correction ≥ 7.55°, the probability of ankle varus incongruence increased 4.86-fold. This may occasion the pathogenesis of ankle pain following TKA.

Preparation and performance of random- and oriented-fiber membranes with core-shell structures via coaxial electrospinning.

The cells and tissue in the human body are orderly and directionally arranged, and constructing an ideal biomimetic extracellular matrix is still a major problem to be solved in tissue engineering. In the field of the bioresorbable vascular grafts, the long-term functional prognosis requires that cells first migrate and grow along the physiological arrangement direction of the vessel itself. Moreover, the graft is required to promote the formation of neointima and the development of the vessel walls while ensuring that the whole repair process does not form a thrombus. In this study, poly (l-lactide-co-ε-caprolactone) (PLCL) shell layers and polyethylene oxide (PEO) core layers with different microstructures and loaded with sodium tanshinone IIA sulfonate (STS) were prepared by coaxial electrospinning. The mechanical properties proved that the fiber membranes had good mechanical support, higher than that of the human aorta, as well as great suture retention strengths. The hydrophilicity of the oriented-fiber membranes was greatly improved compared with that of the random-fiber membranes. Furthermore, we investigated the biocompatibility and hemocompatibility of different functional fiber membranes, and the results showed that the oriented-fiber membranes containing sodium tanshinone IIA sulfonate had an excellent antiplatelet adhesion effect compared to other fiber membranes. Cytological analysis confirmed that the functional fiber membranes were non-cytotoxic and had significant cell proliferation capacities. The oriented-fiber membranes induced cell growth along the orientation direction. Degradation tests showed that the pH variation range had little change, the material mass was gradually reduced, and the fiber morphology was slowly destroyed. Thus, results indicated the degradation rate of the oriented-fiber graft likely is suitable for the process of new tissue regeneration, while the random-fiber graft with a low degradation rate may cause the material to reside in the tissue for too long, which would impede new tissue reconstitution. In summary, the oriented-functional-fiber membranes possessing core-shell structures with sodium tanshinone IIA sulfonate/polyethylene oxide loading could be used as tissue engineering materials for applications such as vascular grafts with good prospects, and their clinical application potential will be further explored in future research.

Retraction of: A005, a novel inhibitor of phosphatidylinositol 3-kinase/mammalian target of rapamycin, prevents osteosarcoma-induced osteolysis.

Osteosarcoma is the most frequent primary bone tumor in children and adolescents. The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is an attractive anticancer target because it plays key roles in the regulation of cell growth, division and differentiation. In this study, we demonstrated high expression of PI3K/mTOR signaling pathway-related genes in patients with osteosarcoma. We thus investigated the effects of A005, a newly synthesized dual PI3K/mTOR inhibitor, on osteosarcoma cells and in a mouse xenograft tumor model. The results confirmed that A005 inhibited the proliferation, migration and invasion of human osteosarcoma cells. In addition, A005 also inhibited receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation and bone resorption in vitro. Therefore, A005 was further applied to a SaOS-2 osteosarcoma-induced mouse osteolysis model. A005 inhibited tumor growth and prevented osteosarcoma-associated osteolysis via modulation of the PI3K/AKT/mTOR pathway. Overall, our results showed that A005 inhibited osteoclastogenesis and prevented osteosarcoma-induced bone osteolysis by suppressing PI3K/AKT/mTOR signaling. These findings indicated that A005 may be a promising candidate drug for the treatment of human osteosarcoma.

Bulleyaconitine A prevents Ti particle-induced osteolysis via suppressing NF-κB signal pathway during osteoclastogenesis and osteoblastogenesis.

Balanced bone resorption and bone formation are vital for bone homeostasis. Excessive osteoclastic bone resorption in this process can cause a variety of bone disorders including osteoporosis, aseptic prosthetic loosening and tumor associated bone destruction. Bulleyaconitine A (BLA) is a natural compound that has been widely used for pain treatment but its role in osteolysis has not yet been investigated. In this study, we verified for the first time that BLA inhibited osteoclast formation, the mRNA expression of osteoclast-related genes and osteoclastic bone resorption by inhibiting NF-κB signal pathway and downstream NFATc1 expression. Meanwhile, BLA had a stimulatory effect in osteoblast differentiation and mineralization. Furthermore, BLA showed preventive effect in Ti particle-induced osteolysis model in vivo. Together, all our data demonstrated that BLA suppressed osteoclastogenesis and promoted osteoblastogenesis via suppressing NF-κB signal pathway and could be an alternative therapeutic choice against bone loss.

Corrigendum: Dihydroartemisinin prevents breast cancer-induced osteolysis via inhibiting both breast cancer cells and osteoclasts.

This corrects the article DOI: 10.1038/srep19074.

Dihydroartemisinin prevents breast cancer-induced osteolysis via inhibiting both breast caner cells and osteoclasts.

Bone is the most common site of distant relapse in breast cancer, leading to severe complications which dramatically affect the patients' quality of life. It is believed that the crosstalk between metastatic breast cancer cells and osteoclasts is critical for breast cancer-induced osteolysis. In this study, the effects of dihydroartemisinin (DHA) on osteoclast formation, bone resorption, osteoblast differentiation and mineralization were initially assessed in vitro, followed by further investigation in a titanium-particle-induced osteolysis model in vivo. Based on the proved inhibitory effect of DHA on osteolysis, DHA was further applied to MDA-MB-231 breast cancer-induced mouse osteolysis model, with the underlying molecular mechanisms further investigated. Here, we verified for the first time that DHA suppressed osteoclast differentiation, F-actin ring formation and bone resorption through suppressing AKT/SRC pathways, leading to the preventive effect of DHA on titanium-particle-induced osteolysis without affecting osteoblast function. More importantly, we demonstrated that DHA inhibited breast tumor-induced osteolysis through inhibiting the proliferation, migration and invasion of MDA-MB-231 cells via modulating AKT signaling pathway. In conclusion, DHA effectively inhibited osteoclastogenesis and prevented breast cancer-induced osteolysis.