Isoliquiritigenin blunts osteoarthritis by inhibition of bone resorption and angiogenesis in subchondral bone

Isoliquiritigenin (ISL), a natural flavonoid extracted from licorice, has been demonstrated to exert attenuation of osteoclastogenesis and anti-angiogenesis activity in a wide variety of cells. Here, we first evaluated the effects of ISL on pathogenesis of osteoarthritis in a mouse model of OA. The data showed that ISL blunted progression of OA and lowered the Osteoarthritis Research Society International (OARSI)-Modified Making Score and protected the articular cartilage. The thickness of calcified cartilage zone was significantly decreased in ISL-treated ACLT mice compared with vehicle group. ISL increased expression level of lubricin and decreased collagen X (Col X), matrix metalloproteinase-13 (MMP-13). Moreover, ISL reduced aberrant active subchondral bone remodelling, including lowered trabecular pattern factor (Tb.pf) and increased bone volume/tissue volume (BV/TV, %) and thickness of subchondral bone plate (SBP) compared with vehicle-treated group. The results of immunostaining further revealed that ISL directly reduced RANKL-RANK-TRAF6 singling pathway induced osteoclastogenesis, prevented abnormal bone formation through indirect inhibition of TGF-β release. Additionally, ISL exerts anti-angiogenesis effects in subchondral bone through direct suppression of MMP-2. These results indicated that ISL attenuates progression of OA by inhibition of bone resorption and angiogenesis in subchondral bone, indicating that this may be a potential preventive therapy for OA.