MicroRNA-378 contributes to osteoarthritis by regulating chondrocyte autophagy and bone marrow mesenchymal stem cell chondrogenesis.

Osteoarthritis (OA) is the most common joint disease; thus, understanding the pathological mechanisms of OA initiation and progression is critical for OA treatment. MicroRNAs (miRNAs) have been shown to be involved in the progression of osteoarthritis, one candidate is microRNA-378 (miR-378), which is highly expressed in the synovium of OA patients during late-stage disease, but its function and the underlying mechanisms of how it contributes to disease progression remain poorly understood. In this study, miR-378 transgenic (TG) mice were used to study the role of miR-378 in OA development. miR-378 TG mice developed spontaneous OA and also exaggerated surgery-induced disease progression. Upon in vitro OA induction, miR-378 expression was upregulated and correlated with elevated inflammation and chondrocyte hypertrophy. Chondrocytes isolated from articular cartilage from miR-378 TG mice showed impaired chondrogenic differentiation. The bone marrow mesenchymal stem cells (BMSCs) collected from miR-378 TG mice also showed repressed chondrogenesis compared with the control group. The autophagy-related protein Atg2a, as well as chondrogenesis regulator Sox6, were identified as downstream targets of miR-378. Ectopic expression of Atg2a and Sox6 rescued miR-378-repressed chondrocyte autophagy and BMSC chondrogenesis, respectively. Anti-miR-378 lentivirus intra-articular injection in an established OA mouse model was shown to ameliorate OA progression, promote articular regeneration, and repress hypertrophy. Atg2a and Sox6 were again confirmed to be the target of miR-378 in vivo. In conclusion, miR-378 amplified OA development via repressing chondrocyte autophagy and by inhibiting BMSCs chondrogenesis, thus indicating miR-378 may be a potential therapeutic target for OA treatments.

DANCR Mediates the Rescuing Effects of Sesamin on Postmenopausal Osteoporosis Treatment via Orchestrating Osteogenesis and Osteoclastogenesis.

As one of the leading causes of bone fracture in postmenopausal women and in older men, osteoporosis worldwide is attracting more attention in recent decades. Osteoporosis is a common disease mainly resulting from an imbalance of bone formation and bone resorption. Pharmaceutically active compounds that both activate osteogenesis, while repressing osteoclastogenesis hold the potential of being therapeutic medications for osteoporosis treatment. In the present study, sesamin, a bioactive ingredient derived from the seed of Sesamum Indicum, was screened out from a bioactive compound library and shown to exhibit dual-regulating functions on these two processes. Sesamin was demonstrated to promote osteogenesis by upregulating Wnt/ß-catenin, while repressing osteoclastogenesis via downregulating NF-κB signaling . Furthermore, DANCR was found to be the key regulator in sesamin-mediated bone formation and resorption . In an ovariectomy (OVX)-induced osteoporotic mouse model, sesamin could rescue OVX-induced bone loss and impairment. The increased serum level of DANCR caused by OVX was also downregulated upon sesamin treatment. In conclusion, our results demonstrate that sesamin plays a dual-functional role in both osteogenesis activation and osteoclastogenesis de-activation in a DANCR-dependent manner, suggesting that it may be a possible medication candidate for osteoporotic patients with elevated DNACR expression levels.

MicroRNA-378 Suppressed Osteogenesis of MSCs and Impaired Bone Formation via Inactivating Wnt/ß-Catenin Signaling.

MicroRNAs (miRNAs) have been reported to serve as silencers to repress gene expression at post-transcriptional levels. Multiple miRNAs have been demonstrated to play important roles in osteogenesis. MicroRNA (miR)-378, a conserved miRNA, was reported to mediate bone metabolism and influence bone development, but the detailed function and underlying mechanism remain obscure. In this study, the miR-378 transgenic (TG) mouse was developed to study the role of miR-378 in osteogenic differentiation as well as bone formation. The abnormal bone tissues and impaired bone quality were displayed in the miR-378 TG mice, and a delayed healing effect was observed during bone fracture of the miR-378 TG mice. The osteogenic differentiation of mesenchymal stem cells (MSCs) derived from this TG mouse was also inhibited. We also found that miR-378 mimics suppressed, whereas anti-miR-378 promoted osteogenesis of human MSCs. Two Wnt family members, Wnt6 and Wnt10a, were identified as bona fide targets of miR-378, and their expression was decreased by this miRNA, which eventually induced the inactivation of Wnt/ß-catenin signaling. Finally, the short hairpin (sh)-miR-378-modified MSCs were locally injected into the fracture sites in an established mouse fracture model. The results indicated that miR-378 inhibitor therapy could promote bone formation and stimulate the healing process in vivo. In conclusion, miR-378 suppressed osteogenesis and bone formation via inactivating Wnt/ß-catenin signaling, suggesting that miR-378 may be a potential therapeutic target for bone diseases.

Sarcopenia: Current treatments and new regenerative therapeutic approaches.

Sarcopenia is characterized by loss of muscle and reduction in muscle strength that contributes to higher mortality rate and increased incidence of fall and hospitalization in the elderly. Mitochondria dysfunction and age-associated inflammation in muscle are two of the main attributors to sarcopenia progression. Recent clinical trials on sarcopenia therapies such as physical exercise, nutraceutical, and pharmaceutical interventions have revealed that exercise is the only effective strategy shown to alleviate sarcopenia. Unlike nutraceutical and pharmaceutical interventions that showed controversial results in sarcopenia alleviation, exercise was found to restore mitochondria homeostasis and dampen inflammatory responses via a complex exchange of myokines and osteokines signalling between muscle and bone. However, as exercise have limited benefit to immobile patients, the use of stem cells and their secretome are being suggested to be novel therapeutics that can be catered to a larger patient population owing to their mitochondria restoration effects and immune modulatory abilities. As such, we reviewed the potential pros and cons associated with various stem cell types/secretome in sarcopenia treatment and the regulatory and production barriers that need to be overcome to translate such novel therapeutic agents into bedside application. Translational potential: This review summarizes the causes underlying sarcopenia from the perspective of mitochondria dysfunction and age-associated inflammation, and the progress of clinical trials for the treatment of sarcopenia. We also propose therapeutic potential of stem cell therapy and bioactive secretome for sarcopenia.

Vasoactive Intestinal Peptide Stimulates Bone Marrow-Mesenchymal Stem Cells Osteogenesis Differentiation by Activating Wnt/ß-Catenin Signaling Pathway and Promotes Rat Skull Defect Repair.

Bone defect regeneration is a complex process that involves the coordination of a variety of different type of cells. As bone tissues are innervated and rich in nerve fibers, the neuropeptides released from various never fibers could regulate bone development, metabolism, and remodeling. Among all the neuropeptides, vasoactive intestinal peptide (VIP) could modulate the functions of both osteoblasts and osteoclasts, and may play a vital role in bone marrow mesenchymal stem cell (BMSC) osteogenesis during bone repair. In this study, we investigated the role of VIP in bone formation and the mechanisms of VIP in mediating BMSC osteogenic differentiation, and its possibility in clinical application of bone defect reconstruction. Our in vitro study results indicated that VIP promoted BMSC osteogenic differentiation by activating Wnt/ß-catenin signaling pathway in BMSCs. VIP could also stimulate tube formation of EA.hy926 endothelial cell and increase vascular endothelial growth factor (VEGF) expression in BMSCs. Furthermore, in the rat skull defect model, VIP-conjugated functionalized hydrogel significantly enhanced cranial bone defect repair compared with the control group, with increased bone formation and angiogenesis. Taken together, as a member of neuropeptides, VIP could promote the BMSCs osteogenesis and angiogenesis differentiation in vitro and stimulate bone repair in vivo by activating Wnt/ß-catenin signaling pathway. The knowledge obtained from this study emphasized the close association between innervation and bone repair process, and VIP may be a potential therapeutic agent for augmenting bone repair.