The therapeutic potential of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) for various diseases and tissue repair is attracting attention. Here, EVs from conditioned medium of human bone marrow MSCs at passage 5 (P5) and passage 12 (P12) were analysed using mouse Achilles tendon rupture model and lectin microarray. P5 MSC-EVs accelerated Achilles tendon healing compared with P12 MSC-EVs. Fucose-specific lectin TJA-II was indicated as a glycan marker for therapeutic MSC-EVs. The present study demonstrated that early passaged MSC-EVs promote Achilles tendon healing compared with senescent MSC-EVs. Glycans on MSC-EVs might provide useful tools to establish a quality control and isolation system for therapeutic MSC-EVs in regenerative medicine.

Background Animal models of spontaneous osteoarthritis (OA) are sparse and not well characterized. The purpose of the present study is to examine OA-related changes and mechanisms in senescence-accelerated mouse prone 8 (SAMP8) that displays a phenotype of accelerated aging.  Methods Knees of male SAMP8 and SAM-resistant 1 (SAMR1) mice as control from 6 to 33 weeks of age were evaluated by histological grading systems for joint tissues (cartilage, meniscus, synovium, and subchondral bone), and µCT analysis. Gene expression patterns in articular cartilage were analyzed by real-time PCR. Immunohistochemistry was performed for OA-related factors, senescence markers, and apoptosis. Results Starting at 14 weeks of age, SAMP8 exhibited mild OA-like changes such as proteoglycan loss and cartilage fibrillation. From 18 to 33 weeks of age, SAMP8 progressed to partial or full-thickness defects with exposure of subchondral bone on the medial tibia and exhibited synovitis. Histological scoring indicated significantly more severe OA in SAMP8 compared with SAMR1 from 14 weeks [median (interquartile range): SAMR1: 0.89 (0.56–1.81) vs SAMP8: 1.78 (1.35–4.62)] to 33 weeks of age [SAMR1: 1.67 (1.61–1.04) vs SAMP8: 13.03 (12.26–13.57)]. Subchondral bone sclerosis in the medial tibia, bone mineral density (BMD) loss of femoral metaphysis, and meniscus degeneration occurred much earlier than the onset of cartilage degeneration in SAMP8 at 14 weeks of age. Conclusions SAMP8 are a spontaneous OA model that is useful for investigating the pathogenesis of primary OA and evaluating therapeutic interventions.

Tendon is a fibrous connective tissue, that is, transmitting the forces that permit body movement. However, tendon/ligament biology is still not fully understood and especially, the role of miRNAs in tendon/ligament is sparse and uncharacterized in in vivo models. The objectives of this study were to address the function of DICER using mice with tendon/ligament-specific deletion of Dicer (Dicer conditional knockout; cKO), and to identify key miRNAs in tendon/ligament. Dicer cKO mice exhibited hypoplastic tendons through structurally abnormal collagen fibrils with downregulation of tendon-related genes. The fragility of tendon did not significantly affect the tensile strength of tendon in Dicer cKO mice, but they showed larger dorsiflexion angle in gait compared with Control mice. We identified two miRNAs, miR-135a and miR-1247, which were highly expressed in the Achilles tendon of Control mice and were downregulated in the Achilles tendon of Dicer cKO mice compared with Control mice. miR-135a mimic increased the expression of tendon-related genes in injured Achilles tendon-derived fibroblasts. In this study, Dicer cKO mice exhibited immature tendons in which collagen fibrils have small diameter with the downregulation of tendon-related genes such as transcriptional factor, extracellular matrix, and miRNAs. Thus, DICER plays an important role in tendon maturation, and miR-135a may have the potential to become key miRNA for tendon maturation and healing.

Osteoarthritis (OA), the most prevalent aging-related joint disease, is characterized by insufficient extracellular matrix synthesis and articular cartilage degradation and is caused by various risk factors including aging and traumatic injury. Most microRNAs (miRNAs) have been associated with pathogenesis of osteoarthritis (OA) using in vitro models. However, the role of many miRNAs in skeletal development and OA pathogenesis is uncharacterized in vivo using genetically modified mice. Here, we focused on miR-23–27–24 clusters. There are two paralogous miR-23–27–24 clusters: miR-23a-27a-24–2 (miR-23a cluster) and miR-23b-27b-24–1 (miR-23b cluster). Each miR-23a/b, miR-24, and miR-27a/b is thought to function coordinately and complementary to each other, and the role of each miR-23a/b, miR-24, and miR-27a/b in OA pathogenesis is still controversial. MiR-23a/b clusters are highly expressed in chondrocytes and the present study examined their role in OA. We analyzed miRNA expression in chondrocytes and investigated cartilage-specific miR-23a/b clusters knockout (Col2a1-Cre; miR-23a/bflox/flox: Cart-miR-23clus KO) mice and global miR-23a/b clusters knockout (CAG-Cre; miR-23a/bflox/flox: Glob-miR-23clus KO) mice. Knees of Cart- and Glob-miR-23a/b clusters KO mice were evaluated by histological grading systems for knee joint tissues using aging model (12 and/or 18 month-old) and surgically-induced OA model. miR-23a/b clusters were among the most highly expressed miRNAs in chondrocytes. Skeletal development of Cart- and Glob-miR-23clus KO mice was grossly normal although Glob-miR-23clus KO had reduced body weight, adipose tissue and bone density. In the aging model and surgically-induced OA model, Cart- and Glob-miR-23clus KO mice exhibited mild OA-like changes such as proteoglycan loss and cartilage fibrillation. However, the histological scores were not significantly different in terms of the severity of OA in Cart- and Glob-miR-23clus KO mice compared with control mice. Together, miR-23a/b clusters, composed of miR-23a/b, miR-24, miR-27a/b do not significantly contribute to OA pathogenesis.

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