Manoj Ravichandran

Introduction. Osteoporosis is defined as a systemic deterioration of bone tissue causing increased risks for fractures, deformities, and chronic pain.^1,2 Approximately 200 million people suffer from osteoporosis worldwide, with an increasing prevalence in the aging population.³ The potential to use MSCs as a therapeutic option for osteoporosis is supported, yet is associated with significant drawbacks such as safety and manufacturing.^1,2 Exosomes are being explored as an alternative therapeutic option as MSCs mechanism of action rely on these secreted factors to modify the environment and recruit resident cells to repair the degenerated tissue.^2,4 It was found that osteoporotic MSCs show enhanced expression of genes involved in osteoclastogenesis and inhibit the Wnt/b-catenin pathway.⁴ The aim of this work was to analyze the role of BM-MSC derived exosomes in regulating the Wnt/b-catenin pathway and identify secreted factors that promote osteoblast proliferation to stimulate bone regeneration.⁵ Methods. BM-MSCs were isolated from the hindlimbs of Sprague Dawley rats and phenotypically characterized using antibodies to different CD antigens and flow cytometry. Exosomes were extracted by centrifugation. After BM-MSC derived exosomal treatment, expression of genes was analyzed by qRT-PCR and proteins of interest by Western blot. By determining the relative expressions of osteogenic factors compared to adipogenic factors, the expression of signaling pathway proteins, and the targets of different microRNA, data was gathered upon how exosomal therapy influences the signaling pathways and the differentiation pathway of MSCs. Results. miR-127-3p, was enriched in BM-MSCs derived exosomes, blocking overexpression of CDH-11, an osteoarthritic protein that enhances expression of b-catenin promoting chondrocyte damage and progression of osteoarthritis.⁶ miR-214, highly expressed in osteoporotic patients, inhibits b-catenin which diminishes osteogenic gene expressions (Runx2) and enhances adipogenic genes (C/EBP-a) favoring an adipogenic differentiation pathway, but knockdown of miR-214 reverses the effects and enhances osteogenesis.⁷ BM-MSCs derived exosomes activate the MAPK pathway to aid in osteoblast proliferation from the hFOB cell line by increasing levels of p-JNK and p-p38 levels.⁸ Irradiated BM-MSCs had diminished levels of b-catenin resulting in enhanced adipogenic factors (PPAR-g) and decreased osteogenic factors (Runx2), but BM-MSC derived exosomes promote b-catenin expression and restore the balance between adipogenic and osteogenic differentiation.⁹ Conclusion. Studies have found that BM-MSCs derived exosomes can regulate the Wnt/b-catenin pathway and its role in bone metabolism with increased levels of b-catenin contributing to greater levels of osteogenic factors and decreased adipogenic factors, yet this can exacerbate other diseases as seen in osteoarthritis from Dong J et al⁶. Therefore, it can be stated that further exploration and studies of the Wnt/b-catenin pathway and exosomal treatment in osteoporosis need to be conducted, but does demonstrate a promising therapeutic option

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