RNA interference-based osteoanabolic therapy for osteoporosis by a bone-formation surface targeting delivery system.

RNA interference (RNAi)-based gene therapy that promotes anabolic bone formation is an effective approach for addressing osteoporosis. However, the selection of target gene and tissue-specific delivery systems has hindered the progression of this strategy. In this study, we identified casein kinase-2 interacting protein-1 encoding gene (Ckip-1), a negative regulator of bone formation, as an effective target of small interfering RNAs (siRNAs) for improving bone mass. Moreover, an impressive (DSS)6-Liposome (Lipos) nanoparticle system that could target the bone formation surface was synthesized to enhance the delivery of Ckip-1 siRNA to osteogenic lineage cells. The in vitro results confirmed that the (DSS)6-Lipos system could efficaciously improve the intracellular delivery of Ckip-1 siRNA without obvious cell toxicity. The in vivo application of the delivery system showed specific accumulation of siRNA in osteogenic cells located around the bone formation surface. Bone-related analysis indicated increased bone mass and improved bone microarchitecture in mice with ovariectomy-induced osteoporosis. Moreover, the biomechanical characteristics of the tibia were enhanced significantly, indicating increased resistance to fragile fracture induced by osteoporosis. Thus, (DSS)6-Lipos-Ckip-1 siRNA-based osteoanabolic therapy may be a promising option for the treatment of osteoporosis.

CKIP-1-Loaded Cartilage-Affinitive Nanoliposomes Reverse Osteoarthritis by Restoring Chondrocyte Homeostasis.

Osteoarthritis (OA) is a chronic joint disease characterized by cartilage imbalance and disruption of cartilage extracellular matrix secretion. Identifying key genes that regulate cartilage differentiation and developing effective therapeutic strategies to restore their expression is crucial. In a previous study, we observed a significant correlation between the expression of the gene encoding casein kinase-2 interacting protein-1 (CKIP-1) in the cartilage of OA patients and OA severity scores, suggesting its potential involvement in OA development. To test this hypothesis, we synthesized a chondrocyte affinity plasmid, liposomes CKIP-1, to enhance CKIP-1 expression in chondrocytes. Our results demonstrated that injection of CAP-Lipos-CKIP-1 plasmid significantly improved OA joint destruction and restored joint motor function by enhancing cartilage extracellular matrix (ECM) secretion. Histological and cytological analyses confirmed that CKIP-1 maintains altered the phosphorylation of the signal transduction molecule SMAD2/3 of the transforming growth factor-ß (TGF-ß) pathway by promoting the phosphorylation of the 8T, 416S sit. Taken together, this work highlights a novel approach for the precise modulation of chondrocyte phenotype from an inflammatory to a noninflammatory state for the treatment of OA and may be broadly applicable to patients suffering from other arthritic diseases.

A viscoelastic PEGylated poly(glycerol sebacate)-based bilayer scaffold for cartilage regeneration in full-thickness osteochondral defect.

Defects of either articular cartilage or subchondral bone would destroy the structural integrity and functionality of the joint. Reconstruction of osteochondral defects requires difunctional scaffolds that simultaneously induce cartilage and subchondral bone morphogenesis, however, high-performance cartilage reconstructive scaffolds remain a considerable challenge. In this study, a solvent-free urethane crosslinking and spontaneous pore-forming procedure under room temperature was proposed and optimized to produce PEGylated poly(glycerol sebacate) (PEGS) scaffolds with controllable crosslinking degrees and hierarchical macro-/micro-porosities. Based on the economical and feasible preparative approach, the viscoelastic PEGS-12h with low crosslinking degree was demonstrated to significantly stimulate chondrogenic differentiation, maintain chondrocyte phenotype and enhance cartilage matrix secretion compared to elastic polymer with high crosslinking degree, emphasizing the importance of matrix viscoelasticity in cartilage regeneration. On this basis, the viscoelastic low-crosslinked PEGS-12h was combined with the well-acknowledged osteoinductive mesoporous bioactive glass (MBG) to construct a difunctional PEGS/MBG bilayer scaffold, and evaluated in a full-thickness osteochondral defect model in vivo. The PEGS/MBG bilayer scaffold successfully reconstructed well-integrated articular hyaline cartilage and its subchondral bone in 12 weeks, exhibiting extraordinary regenerative efficiency. The results indicated that the viscoelastic PEGS scaffold and PEGS/MBG bilayer scaffold proposed in this study made an excellent candidate for cartilage and osteochondral regeneration, and was expected for clinical translation in the future.