A novel negative regulatory mechanism of Smurf2 in BMP/Smad signaling in bone  

作　　者：Junichi Kushioka Takashi Kaito Rintaro Okada Hiroyuki Ishiguro Zeynep Bal Joe Kodama Ryota Chijimatsu Melanie Pye Masahiro Narimatsu Jeffrey LWrana Yasumichi Inoue Hiroko Ninomiya Shin Yamamoto Takashi Saitou Hideki Yoshikawa Takeshi Imamura 

机构地区：[1]Department of Orthopaedic Surgery,Osaka University Graduate School of Medicine,2-2 Yamadaoka,Suita,Osaka 565-0871,Japan [2]Bone and Cartilage Regenerative Medicine,The University of Tokyo,7-3-1,Hongo,Bunkyo-ku,Tokyo 113-8655,Japan [3]Centre for Systems Biology,Lunenfeld-Tanenbaum Research Institute,Mount Sinai Hospital,600 University Ave,Toronto,ON M5G 1X5,Canada [4]Department of Cell Signaling,Graduate School of Pharmaceutical Sciences,Nagoya City University,3-1 Tanabe-dori,Mizuho-ku,Nagoya,Aichi 467-8603,Japan [5]Department of Molecular Medicine for Pathogenesis,Ehime University Graduate School of Medicine,454 Shitsukawa,Toon,Ehime 791-0295,Japan [6]Department of Gastroenterology and Metabology,Ehime University Graduate School of Medicine,454 Shitsukawa,Toon,Ehime 791-0295,Japan [7]Translational Research Center,Ehime University Hospital,454 Shitsukawa,Toon,Ehime 791-0295,Japan

出　　处：《Bone Research》2020年第4期429-438,共10页骨研究（英文版）

基　　金：the JSPS Grant-in-Aid(C)grant number 17K11005;the JSPS bilateral Joint Research Project grant number 1007397 to T.K.,MEXT/JSPS grant number JP19K12218 to T.S.,MEXT/JSPS grant number JP15H05952(“Resonance Bio”)to T.S.and T.I.,and MEXT/JSPS KAKENHI grant number JP16H06280(“Advanced Bioimaging Support”)。

摘　　要：Transforming growth factor-β(TGF-β)and bone morphogenetic protein(BMP)play important roles in bone metabolism.Smad ubiquitination regulatory factors(Smurfs)regulate TGF-β/BMP signaling via ubiquitination,resulting in degradation of signaling molecules to prevent excessive activation of TGF-β/BMP signaling.Though Smurf2 has been shown to negatively regulate TGF-β/Smad signaling,its involvement in BMP/Smad signaling in bone metabolism has not been thoroughly investigated.In the present study,we sought to evaluate the role of Smurf2 in BMP/Smad signaling in bone metabolism.Absorbable collagen sponges containing 3μg of recombinant human BMP2(rhBMP2)were implanted in the dorsal muscle pouches of wild type(WT)and Smurf2−/−mice.The rhBMP2-induced ectopic bone in Smurf2−/−mice showed greater bone mass,higher mineral apposition and bone formation rates,and greater osteoblast numbers than the ectopic bone in WT mice.In WT mice,the ectopic bone consisted of a thin discontinuous outer cortical shell and scant inner trabecular bone.In contrast,in Smurf2−/−mice,the induced bone consisted of a thick,continuous outer cortical shell and abundant inner trabecular bone.Additionally,rhBMP2-stimulated bone marrow stromal cells(BMSCs)from Smurf2−/−mice showed increased osteogenic differentiation.Smurf2 induced the ubiquitination of Smad1/5.BMP/Smad signaling was enhanced in Smurf2−/−BMSCs stimulated with rhBMP2,and the inhibition of BMP/Smad signaling suppressed osteogenic differentiation of these BMSCs.These findings demonstrate that Smurf2 negatively regulates BMP/Smad signaling,thereby identifying a new regulatory mechanism in bone metabolism.

关 键 词：SMURF2 METABOLISM INVOLVEMENT 

分 类 号：R329.2[医药卫生—人体解剖和组织胚胎学]