Fat Extract Modulates Calcium Signaling and Protects Against Hyperactive Osteoclastogenesis in Bone Remodeling with Antioxidant Capacity

Abstract

Osteoclasts are cells which are primarily involved in bone remodeling and osteolytic bone diseases. Hyperactive osteoclastogenesis leads to pathological bone loss and microarchitectural deterioration, particularly in postmenopausal osteoporosis. However, given the limitations of current first-line osteoclast inhibitors, there is an urgent need for a novel antiresorptive agent with higher efficiency and fewer side effects. Cell-free fat extract (CEFFE) is the liquid fraction obtained from human adipose tissues, which are enriched with a variety of cytokines and growth factors. This study aims to explore its pharmaceutical effect on hyperactive osteoclast formation in vivo and in vitro. CEFFE exhibits excellent potentials to attenuate osteoclast-associated bone loss in an ovariectomy (OVX) mouse model and to inhibit RANKL-induced osteoclastogenesis in primary bone marrow-derived monocytes. Furthermore, the cationic protein fraction of CEFFE (CEFFE-Cation) is identified as the main inhibitory component in osteoclast formation assay. Excessive reactive oxygen species (ROS) production is the main cause of osteoclast overactivation. According to LC-MS/MS analysis, the CEFFE-Cation fraction mainly consists of various antioxidant enzymes, extracellular matrix, and secreted cytokines, which endow it with a superior antioxidant capacity. Ca2+ signaling contributes to osteoclast maturation. In addition to scavenging ROS, CEFFE-Cation is also capable of mitigating Ca2+ oscillation, calcineurin activation, and subsequent NFATc1 nuclear translocation during osteoclastogenesis. Overall, this study elucidates the promising translational potential of CEFFE as a next-generation personalized antiresorptive agent for osteolytic bone disease treatment.