Current Progress on MicroRNA-Based Gene Delivery in the Treatment of Osteoporosis and Osteoporotic Fracture

Abstract

Emerging evidence demonstrates that microRNAs, as important endogenous posttranscriptional regulators, are essential for bone remodeling and regeneration. Undoubtedly, microRNA-based gene therapies show great potential to become novel approaches against bone-related diseases, including osteoporosis and associated fractures. The major obstacles for continued advancement of microRNA-based therapies in clinical application include their poor in vivo stability, nonspecific biodistribution, and unwanted side effects. Appropriate chemical modifications and delivery vectors, which improve the biological performance and potency of microRNA-based drugs, hold the key to translating miRNA technologies into clinical practice. Thus, this review summarizes the current attempts and existing deficiencies of chemical modifications and delivery systems applied in microRNA-based therapies for osteoporosis and osteoporotic fractures to inform further explorations.

Figure 1

Mechanism of bone remodeling. Under basal conditions, the bone surface is covered by bone lining cells. Local microdamage will recruit hematopoietic stem cell-derived preosteoclasts to differentiate into mature osteoclasts. Mature osteoclasts absorb bone mineral and matrix. After the resorption phase, MSCs are recruited to differentiate into mature osteoblasts, which secrete and mineralize new bone matrix. Once the microdamage is restored, mature osteoblasts will terminally differentiate into either bone lining cells or osteocytes. Type H vessels also participate in the bone remodeling process, which help form a regulation loop comprising preosteoclasts, osteoblasts, and CD31^hiEmcn^hi ECs. PDGF-BB secreted by preosteoclasts, as well as activated endothelial Notch and HIF-1α signals, induces CD31^hiEmcn^hi EC proliferation and vessel growth in bone. Notch activity stimulates the expression of endothelial Noggin, whereas PDGF-BB induces CD31^hiEmcn^hi ECs to secrete S1P. Then, increased Noggin and S1P promote osteoblast differentiation and thereby osteogenesis. Meanwhile, the augmented osteoblast numbers secrete vascular endothelial growth factor (VEGF) and positively regulate type H vessel proliferation.