Drug delivery for osteoarthritis (OA) treatment is a continuous challenge because of their poor bioavailability and rapid clearance in joints. Intra-articular (IA) drug delivery is a common strategy and its therapeutic effects depend mainly on the efficacy of the drug-delivery system used for OA therapy. Different types of IA drug-delivery systems, such as microspheres, nanoparticles, and hydrogels, have been rapidly developed over the past decade to improve their therapeutic effects. With the continuous advancement in OA mechanism research, new drugs targeting specific cell/signaling pathways in OA are rapidly evolving and effective drug delivery is critical for treating OA. In this review, recent advances in various IA drug-delivery systems for OA treatment, OA targeted strategies, and related signaling pathways in OA treatment are summarized and analyzed based on current publications. 

/pdf/knee-osteoarthritis-therapy-recent-advances-in-intra-2klgz6a7.pdf

Knee Osteoarthritis Therapy: Recent Advances in Intra-Articular Drug Delivery Systems

Chondrosarcoma is the second most frequent bone sarcoma. Due to the inherent chemotherapy and radiotherapy resistance and absence of known therapeutic targets, clinical management is limited to surgical resection. Consequently, patients with advanced disease face a poor prognosis. Hence, elucidating regulatory networks governing chondrosarcoma pathogenesis is vital for development of effective therapeutic strategies. Here, miRNA and mRNA next generation sequencing of different subtypes of human chondrogenic tumors in combination with in silico bioinformatics tools were performed with the aim to identify key molecular factors. We identified miR-143/145 cluster levels to inversely correlate with tumor grade. This deregulation was echoed in the miRNA plasma levels of patients and we provided the first evidence that circulating miR-145 is a potential noninvasive diagnostic biomarker and can be valuable as an indicator to improve the currently challenging diagnosis of cartilaginous bone tumors. Additionally, artificial upregulation of both miRNAs impelled a potent tumor suppressor effect in vitro and in vivo in an orthotopic xenograft mouse model. A combined in silico/sequencing approach revealed FSCN1 as a direct target of miR-143/145, and its depletion phenotypically resembled miR-143/145 upregulation in vitro. Last, FSCN1 is a malignancy-promoting factor associated with aggressive chondrosarcoma progression. Our findings underscore miR-143/145/FSCN1 as important players in chondrosarcoma and may potentially open new avenues for specific therapeutic intervention options. © 2020 American Society for Bone and Mineral Research.

https://asbmr.onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.3976

The miR-143/145 Cluster, a Novel Diagnostic Biomarker in Chondrosarcoma, Acts as a Tumor Suppressor and Directly Inhibits Fascin-1

MircoRNA-143-3p regulating ARL6 is involved in the cadmium-induced inhibition of osteogenic differentiation in human bone marrow mesenchymal stem cells.

Abstract Drug delivery for osteoarthritis (OA) treatment is a continuous challenge because of their poor bioavailability and rapid clearance in joints. Intra-articular (IA) drug delivery is a common strategy and its therapeutic effects depend mainly on the efficacy of the drug-delivery system used for OA therapy. Different types of IA drug-delivery systems, such as microspheres, nanoparticles, and hydrogels, have been rapidly developed over the past decade to improve their therapeutic effects. With the continuous advancement in OA mechanism research, new drugs targeting specific cell/signaling pathways in OA are rapidly evolving and effective drug delivery is critical for treating OA. In this review, recent advances in various IA drug-delivery systems for OA treatment, OA targeted strategies, and related signaling pathways in OA treatment are summarized and analyzed based on current publications.

https://www.dovepress.com/getfile.php?fileID=80519

Human bone marrow-derived mesenchymal stem cells (hBMSCs) have chondrocyte differentiation potential and are considered to be a cell source for cell-transplantation-mediated repair of cartilage defects, including those associated with osteoarthritis (OA). However, chondrocyte hypertrophic differentiation is a major obstacle for the application of hBMSCs in articular cartilage defect treatment. We have previously shown that microRNA-27b (miR-27b) inhibits hypertrophy of chondrocytes from rat knee cartilage. In this study, we investigated the role of miR-27b in chondrocyte hypertrophic differentiation of hBMSCs. Chondrogenic marker and microRNA expression in hBMSC chondrogenic pellets were evaluated using RT-qPCR and immunohistochemistry. The hBMSCs were transfected with miR-27b before inducing differentiation. Gene and protein expression levels were analyzed using RT-qPCR and western blot. Coimmunoprecipitation was used to confirm interaction between CBFB and RUNX2. Luciferase reporter assays were used to demonstrate that CBFB is a miR-27b target. Chondrogenic differentiation was evaluated in hBMSCs treated with shRNA targeting CBFB. Chondrogenic hBMSC pellets overexpressing miR-27b were implanted into cartilage lesions in model rats; therapeutic effects were assessed based on histology and immunohistochemistry. The hBMSCs showed typical MSC differentiation potentials. During chondrogenic differentiation, collagen 2 and 10 (COL2 and COL10), SOX9, and RUNX2 expression was upregulated. Expression of miR-140, miR-143, and miR-181a increased over time, whereas miR-27b and miR-221 were downregulated. Cartilage derived from hBMSC and overexpressing miR-27b exhibited higher expression of COL2 and SOX9, but lower expression of COL10, RUNX2, and CBFB than did the control cartilage. CBFB and RUNX2 formed a complex, and CBFB was identified as a novel miR-27b target. CBFB knockdown by shRNA during hBMSC chondrogenic differentiation led to significantly increased COL2 and SOX9 expression and decreased COL10 expression. Finally, miR-27b-overexpressing hBMSC chondrogenic pellets had better hyaline cartilage morphology and reduced expression of hypertrophic markers and tend to increase repair efficacy in vivo. MiR-27b plays an important role in preventing hypertrophic chondrogenesis of hBMSCs by targeting CBFB and is essential for maintaining a hyaline cartilage state. This study provides new insights into the mechanism of hBMSC chondrocyte differentiation and will aid in the development of strategies for treating cartilage injury based on hBMSC transplantation.

/pdf/microrna-27b-targets-cbfb-to-inhibit-differentiation-of-3xsg35r3qt.pdf

MicroRNA-27b targets CBFB to inhibit differentiation of human bone marrow mesenchymal stem cells into hypertrophic chondrocytes

Objective The aim of this study was to explore the role of microRNA-143-3p (miR-143-3p) in cartilage injury, and to investigate the possible underlying mechanism. Materials and methods A chondrogenic differentiation cell model was established in bone marrow mesenchymal stem cells (BMSCs). The mRNA expression levels of runt-related transcription factor 2 (RUNX2), miR-143-3p and bone morphogenetic protein 2 (BMPR2) in BMSCs were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) after 0 d, 5 d and 10 d, respectively. Mesenchymal stem cells (MSCs) were transfected with miR-143-3p mimics and its control in accordance with the liposome method. Alcian blue colorimetric assay was used to evaluate proteoglycan deposition of MSCs. Meanwhile, qRT-PCR and Western blot were performed to analyze the expression levels of ACAN and COL2A1. Luciferase reporter gene assay was applied to verify the binding status of miR-143-3p and BMPR2 3'UTR. Also, proteoglycan deposition and the expression of ACAN and COL2A1 were detected after simultaneous transfection of miR-143-3p mimics and BMPR2 overexpression plasmid. Results 0 d, 5 d and 10 d after inducing cartilage differentiation, the mRNA expression levels of RUNX2 and BMPR2 were markedly increased. However, the expression level of miR-143-3p was significantly decreased with the prolongation of induction period. After transfection with miR-143-3p mimics, the level of miR-143-3p in MSCs was remarkably increased. Alcian blue colorimetric assay and staining assay showed that the deposition of proteoglycans in the mimics group was significantly lower than that of the control group. Meanwhile, after overexpressing miR-143-3p, the levels of cartilage differentiation marker proteins including ACAN and COL2A1 were remarkably reduced. Luciferase report gene assay indicated that miR-143-3p could negatively regulate BMPR2 by binding to its 3'UTR. In addition, overexpression of BMPR2 could strikingly reverse the above effects of overexpressed miR-143-3p. Conclusions During chondrogenic differentiation, the level of miR-143-3p was decreased. Moreover, miR-143-3p could regulate the differentiation process by targeting BMPR2 in BMSCs.

MiR-143-3p regulates early cartilage differentiation of BMSCs and promotes cartilage damage repair through targeting BMPR2.

The Krackow technique has the advantage of high strength, though it is not minimally invasive. The “Locking Block Modified Krackow” (LBMK) peri-tendon fixation technique was designed for minimally invasive surgery. This study aimed to compare the biomechanics of LBMK with Kessler and Percutaneous Achilles Repair System (PARS) techniques using a simulated early rehabilitation program. Thirty-fresh bovine Achilles tendon specimens were randomly assigned to the LBMK, Kessler, and PARS groups (n = 10). In LBMK group, the main suture configuration was the LBMK technique, and the transverse suture was used as the secondary suture configuration. The Kessler group employed three suture configurations, two sagittal, one coronal plane. In the PARS group, two transverse and one locking sutures were placed at either end of the tendon. Each repaired specimen underwent two cyclic loading protocols (20–100 N, 20–190 N), 500 cycles, followed by measurement of the gap between the tendon ends. All specimens underwent a load-to-failure test at a 25 mm/s stretching rate. After the first loading cycle, the average gaps of the LBMK, Kessler and PARS groups were 0.76 ± 0.44 mm, 1.80 ± 0.82 mm, and 2.66 ± 1.04 mm, respectively. The LBMK group had a significantly reduced gap than the other groups (p < 0.01). The LBMK group gaps were all within 2 mm. The Kessler and PARS groups had six, and two specimens within 2 mm, respectively. After the second loading cycle, the average end gaps of the LBMK, Kessler, and PARS groups were 3.68 ± 1.08 mm, 5.70 ± 0.89 mm and 7.59 ± 1.26 mm, respectively. The LBMK group had a significantly reduced average gap than the other groups (p < 0.01). The maximum load-to-failure was highest 732.8 ± 138 N in the LBMK than the other groups (p < 0.01). The biomechanical strength of the LBMK suture was significantly greater than Kessler and PARS. The reduced gap in the LBMK group suggests superior resistance to gap formation, which may occur during early postoperative rehabilitation.

A biomechanical comparison of Achilles tendon suture repair techniques: Locking Block Modified Krackow, Kessler, and Percutaneous Achilles Repair System with the early rehabilitation program in vitro bovine model.

Background Open Giftbox repair of the Achilles tendon has good biomechanical advantages, but it is not minimally invasive. We designed a peritendon fixation technique, the “Locking Block Modified Krackow” (LBMK) technique, to meet minimally invasive needs. This study used a simulated protocol of early rehabilitation to compare the biomechanics of LBMK with those of the Giftbox technique. Methods Twenty fresh bovine Achilles tendon specimens were randomly assigned to either the LBMK group or the Giftbox group. The LBMK technique and the Giftbox technique were used as the main suture configurations, and transverse sutures were used as secondary suture configurations in both groups. Each repaired specimen was subjected to two cyclic loading protocols (20–100 N, 20–190 N). The gapping between the tendon ends was measured after each stage of loading. Finally, all specimens underwent a load-to-failure test at a stretching rate of 25 mm/s. Results After the first loading stage, the mean tendon gapping was 0.76±0.44 mm in the LBMK group and 0.86 ± 0.47 mm in the Giftbox group (p = 0.620). After the second loading test, the average gapping measures of the LBMK and Giftbox groups were 3.8 ± 1.9 mm and 4.2 ± 2.2 mm, respectively (p = 0.466). Finally, the catastrophic load to failure was 732.8 ± 138 N in the LBMK group and 645.5 ± 121 N in the Giftbox group. The difference was statistically significant (p = 0.023). Conclusion Both the LBMK and Giftbox techniques meet the requirements of early rehabilitation, but the suture strength in the LBMK group was significantly higher than that in the Giftbox group.

Achilles tendon rupture repair: Biomechanical comparison of the locking block modified Krackow technique and the Giftbox technique.

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MiR-143-3p regulates early cartilage differentiation of BMSCs and promotes cartilage damage repair through targeting BMPR2.

A biomechanical comparison of Achilles tendon suture repair techniques: Locking Block Modified Krackow, Kessler, and Percutaneous Achilles Repair System with the early rehabilitation program in vitro bovine model.

Achilles tendon rupture repair: Biomechanical comparison of the locking block modified Krackow technique and the Giftbox technique.