Novel treatments for knee osteoarthritis and impaired fracture healing in animal models

Abstract

Osteoarthritis(OA) is the joint degenerative disorder causing pain, cartilage damage, deformity, and disability. With the ageing of the population, OA is becoming a serious medical problem and causing a tremendous social-economic burden. The pathophysiology of OA is still unclear to date. OA was recognized as a "wear and tear" musculoskeletal disorder for a long time. However, recent studies have discovered a straightforward inflammation process in OA development. Visceral obesity can trigger systemic chronic metabolic inflammation. FABP4 is an adipokine abundantly expressed in adipose tissue. It was reported that FABP4 is a novel biomarker for OA. Oral gavage FABP4 inhibitor BMS309403 significantly alleviated the degradation ofcartilage at early OA. The similar effect was found in the FABP4 knocking out (KO) group of mice. The infrapatellar fat pad (IFP) is the largest adipose tissue in the knee. Recent studies have found that the IFP, like other fatty tissue, could secrete soluble factors such as cytokines and adipokines, which may cause cartilage degradation and contribute to OA development. The adipose property of IFP and its proinflammation effect make us hypothesize that it could be the primary source of FABP4. To investigate whether IFP is the possible primary source of FABP4, sample of different body parts were collected from OA patients and non-OA controls. The FABP4 level in SF and plasma was found significantly higher in OA patients, supporting the hypothesis that IFP is most likely to act as the primary source of FABP4. Then, the effect of intraarticular injection of FABP4 inhibitor BMS309403was tested in mice OA model. It was found that local treatment of BMS309403 significantly alleviated OA. About 5% of all fractures are ended with poor healing called impaired fracture healing, causing a substantial loss of mobility for patients and huge socialeconomic burden. Cytokines and growth factors that attract mesenchymal stem cells (MSCs), which proliferate to form woven bone. MSCs from a variety of tissues contain various soluble factors (e.g. cytokines), microvesicles, or exosomes. Recently, MSCs were found in urine, which can be obtained non-invasively in almost unlimited quantities and have properties (e.g. yield, proliferation, and differentiation) comparable to MSCs from umbilical cord blood.Exosomes are nano-sized extracellular vesicles secreted by cells. Exosomes were reported to contain various bioactive factors, including proteins, lipids, and cytokines. Exosomes secreted by several types of cells have been proven to improve fracture healing. However, there is limited data on the application of the USC-derived exosomes to treat critical bone defect. In this study, the ability of exosomes secreted by human USCs (USC-Exos) to promote the fracture healing was evaluated in a rat critical bone defect model. The results show that USC-Exos specifically accelerate migration, tube formation, and endothelial cell proliferation.