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

Abstract

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.

BMSCs‐Derived Exosomes Ameliorate Pain Via Abrogation of Aberrant Nerve Invasion in Subchondral Bone in Lumbar Facet Joint Osteoarthritis

“…Interestingly, we found that BMSC‐exosomes were effective in suppression of RANKL‐RANK‐TRAF6 signaling pathways, as indicated by reduced expression of RANKL and TRAF6‐positive cells in the subchondral bone. These results were consistent with the recent study that inhibition of RANKL‐RANK‐TRAF6 could suppress bone resorption and angiogenesis to blunt OA progression …”

“…These results were consistent with the recent study that inhibition of RANKL-RANK-TRAF6 could suppress bone resorption and angiogenesis to blunt OA progression. 50 Although BMSCs-exosomes attenuated RANKL-RANK-TRAF6 signaling pathways to inhibit the osteoclast activity during bone remodeling, the detailed mechanisms related to the suppression of the aberrant nerve invasion and angiogenesis in subchondral bone has not yet been explored in the current study. In contrast, exosomes regulate target cell effects by cell-to-cell communication, the crosstalk between the BMSCs-Exosomes and various kinds of cells in LFJ.…”

Unique bone marrow blood vessels couple angiogenesis and osteogenesis in bone homeostasis and diseases

“…85 Furthermore, researchers revealed that through different molecular mechanisms, including indirect inhibition of matrix metalloprotein 2 or direct suppression of transforming growth factor beta (TGF-β), VEGF, or angiogenin-1, medications such as halofuginone, isoliquiritigenin, or artesunate could attenuate excessive type H vessel formation and aberrant osteogenesis, which in part would exert a protective effect on the progression of osteoarthritis. [86][87][88]…”

Biochemical Signals Mediate the Crosstalk between Cartilage and Bone in Osteoarthritis

“…A successful drug treatment strategy should be able to affect multiple levels of lesions simultaneously in OA [7,70,71]. Biochemical crosstalk in the osteochondral junction is a core event in the initiation and progression of OA.…”

“…Li et al [72] suggested that artesunate alleviated the excessive release of TGF-β, thereby reducing the number of nestin + MSCs, while promoting the transfer of osterix + osteoprogenitors from the bone marrow to the bone surface to inhibit the TGFβ/Smad2/3 signalling, ultimately inhibiting an ectopic bone formation. Moreover, Ji et al [70] showed that isoliquiritigenin both directly inhibited osteoclastogenesis induced by the RANKL-RANK-TRAF6 signalling and indirectly inhibited the excessive release of TGF-β to block a series of downstream signalling cascades and alleviate an abnormal bone formation in SB. Besides, Zhu et al [7] found that alendronate also impeded osteoclastogenesis to protect against cartilage damage by upregulating the OPG/RANKL ratio and inhibiting chondrocyte catabolic factors in ovariectomised OA mice.…”