No abstract

Osteolysis is an osteolytic lesion featured by enhanced osteoclast formation and potent bone erosion. Lacking of effective regimen for treatment of the pathological process highlights the importance of identifying agents that can suppress the differentiation and function of osteoclast. Artemether is a natural compound derived from Artemisia annua L. and it is popularized for the treatment of malaria. In present study, we demonstrated that artemether could suppress RANKL-induced osteoclastogenesis and expression of osteoclast marker genes such as tartrate-resistant acid phosphatase, cathepsin K, matrix metalloproteinase 9, nuclear factor of activated T-cell cytoplasmic 1, and dendritic cell-specific transmembrane protein. It inhibited the osteoclastic bone resorption in a dose-dependent manner in vitro. Furthermore, artemether attenuated RANKL-induced MAPKs (ERK, JNK, p-38) activity. In addition, we have showed that artemether was able to mitigate bone erosion in a murine model of LPS-induced inflammatory bone loss. Taken together, these findings suggest that artemether reduces inflammatory bone loss via inhibition of MAPKs activation during osteoclast differentiation, and it might be a potential candidate for the treatment of osteoclast-related disorders.

Pyruvate kinase M2 (PKM2) has been wildly verified to modulate glycolysis in tumor cells. However, the role of PKM2 on the glycolysis of osteoarthritis (OA) chondrocytes is still unclear. In present study, we investigate the function of PKM2 on OA chondrocyte glycolysis and the collagen matrix generation in vitro. Results showed that PKM2 was upregulated in OA chondrocytes compared with healthy control chondrocytes. In OA chondrocytes, ATP expression was lower compared with healthy control chondrocytes. Loss-of-function experiment showed that PKM2 knockdown mediated by lentivirus transfection could significantly suppress the glucose consumption and lactate secretion levels and decrease glucose transporter-1 (Glut-1), lactate dehydrogenase A (LDHA), and hypoxia inducible factor 1-alpha (HIF-1α), indicating the inhibition of PKM2 knockdown on glycolysis. Moreover, Cell Counting Kit-8 (CCK-8), flow cytometry, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay showed that PKM2 knockdown inhibited OA chondrocyte proliferation and promoted the apoptosis. Western blot and immunocytochemical staining showed that PKM2 knockdown downregulated the expression levels of COL2A1 and SOX-9. In summary, our results conclude that PKM2 modulates the glycolysis and extracellular matrix generation, providing the vital role of PKM2 on OA pathogenesis and a novel therapeutic target for OA.

Postmenopausal osteoporosis is initiated by estrogen withdrawal and is characterized mainly by over‐activated osteoclastic bone resorption. Targeting TNF receptor‐associated factor 6 (TRAF6) or its downstream signaling pathways to modulate osteoclast formation and function is an appealing strategy for osteoclast‐related disorders. In the present study, we determined the effect of tomatidine, a steroidal alkaloid derived from Solanaceae, on the formation and function of receptor activator of NF‐κB (RANK) ligand‐induced osteoclasts and the underlying mechanism. Tomatidine inhibited osteoclast formation in a dose‐dependent manner and decreased the expression of osteoclast marker genes. Actin ring formation and osteoclastic bone resorption were attenuated in the presence of tomatidine in vitro. Eight weeks after ovariectomy, tomatidine prevented estrogen deficiency‐induced bone loss and restored the mechanical properties of the femur. At the molecular level, tomatidine abrogated phosphorylation of c‐Jun N‐terminal kinase (JNK)/p38, NF‐κB, and protein kinase B (Akt) pathway proteins by suppressing RANK expression, inhibiting the binding of TRAF6 to RANK, and downregulating the osteoclastogenesis marker‐related protein expression. In summary, these data demonstrated that tomatidine attenuated osteoclast formation and function by modulating multiple TRAF6‐mediated pathways. Therefore, tomatidine could be a novel candidate for the treatment of osteoclast‐related disorders, including osteoporosis.—Hu, B., Sun, X., Yang, Y., Ying, Z., Meng, J., Zhou, C., Jiang, G., Li, S., Wu, F., Zhao, X., Zhu, H., Wu, H., Cai, X., Shi, Z., Yan, S. Tomatidine suppresses osteoclastogenesis and mitigates estrogen deficiency‐induced bone mass loss by modulating TRAF6‐mediated signaling. FASEB J. 33,2574–2586 (2019). http://www.fasebj.org

Osteolysis is characterized by overactivated osteoclast formation and potent bone resorption. It is enhanced in many osteoclast‐related diseases including osteoporosis and periprosthetic osteolysis. The shortage of effective treatments for these pathological processes emphasizes the importance of screening and identifying potential regimens that could attenuate the formation and function of osteoclasts. Dehydrocostus lactone (DHE) is a natural sesquiterpene lactone containing anti‐inflammatory properties. Here, we showed that DHE suppressed receptor activator of nuclear factor‐κB ligand (RANKL)‐induced osteoclast formation and osteoclast marker gene expression. It also inhibited F‐actin ring formation and bone resorption in a dose‐dependent manner in vitro. Moreover, DHE inhibited the RANKL‐induced phosphorylation of NF‐κB, mitigated bone erosion in vivo in lipopolysaccharide‐induced inflammatory bone loss model and particle‐induced calvarial osteolysis model. Together, these results suggest that DHE reduces osteoclast‐related bone loss via the modulation of NF‐κB activation during osteoclastogenesis indicating that it might be a useful treatment for osteoclast‐related skeletal disorders.

No abstract

Previous studies have shown that Low intensity pulsed ultrasound(LIPUS) prevents polyethylene-debris-induced periprosthetic loosening in vivo, but the details of the mechanism by which it does so remain unclear. In this article, we used polyethylene debris induced RAW 264.7 cells as the in vitro model, and tested the effect of LIPUS on this model. Changes in the level of inflammatory cytokines, cell proliferation, and apoptosis were assessed. Gene overexpression and siRNA technique were applied, and the levels of expression of FBXL2, TRAF6, ERK, and related inflammatory cytokines were also measured. Results indicated that FBXL2-mediated TRAF6 ubiquitination and degradation also plays an important role in aseptic periprosthetic loosening process, and LIPUS prevents such loosening by strengthening this pathway.

Therapeutic, Level IV.