title: Setd2 is associated with strontium-induced bone regeneration.
abstract: Strontium Ranelate has been utilized as a preventative treatment option for osteoporosis with the release of Sr ions having a direct effect on preventing osteoclast activation and promoting osteoblast differentiation. Previously our group has prepared and characterized a porous Sr-mesoporous bioactive glass (Sr-MBG) scaffold demonstrating its ability to enhance new bone formation when compared to MBG alone. The goal of the present study was to elucidate the bone-inducing properties of Sr by utilizing RNA-seq on in vivo tissue samples to investigate potential target genes responsible for Sr-induced new bone formation. The results demonstrated an increased expression and affiliation of Setd2 in the Sr-MBG group when compared to MBG group alone. Immunofluorescent staining further demonstrated a localization of Setd2 and H3K36me3 in Runx2-positive cells in defects treated with Sr-MBG scaffolds. It was detected that specifically MAPK pathway was activated in MG63 stimulated by Sr. To verify the role of Setd2 in bone formation in the presence of SrCl2, Setd2 was knocked-down and overexpressed in MG63 with/without SrCl2stimulation. The result showed that Setd2 plays a positive role in osteoblast differentiation which was enhanced by SrCl2. Furthermore, it was found that Setd2 regulated the activation of ERK, which set up a positive feedback in the osteoblast differentiation process. Based on these findings, it was shown that Setd2 has an active role in osteoblast differentiation. As a histone methylase, Setd2 may also turn to be an epigenetic target for new treatment options of osteoporosis.
  
  
  
  Our research group recently demonstrated that the combination of MBG scaffolds with Sr, efficiently promoted bone regeneration in rat femoral defects even in severely compromised osteoporotic animals, however, the epigenetic mechanism by which Sr ions function to promote bone generation remains unclear. This study showed an increased expression and affiliation of Setd2 and H3K36me3. In vitro, the increased expression of Setd2 promoted osteoblastic differentiation of MG63 stimulated by SrCl2 in MAPK-dependent way, which activated ERK in turn leading to a positive feedback. Based on these findings, it was shown that Setd2 has an active role in osteoblast differentiation and may also turn to be an epigenetic target for new treatment options of osteoporosis and the development of novel bone regeneration scaffold.
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, China.
authors.forename: Xiaoshi
authors.initials: X
authors.lastname: Jia
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease, Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Qiaoyun
authors.initials: Q
authors.lastname: Long
authors.affiliation: Department of Periodontology, Cell Therapy Institute, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, Florida, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Miron
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, China.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Yin
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, China. Electronic address: zyf@whu.edu.cn.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease, Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China. Electronic address: wumin@whu.edu.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
mesh_terms: D000818:Animals; D001861:Bone Regeneration; D016025:Bone Transplantation / Q000295:instrumentation* / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants / Q000008:administration & dosage; D005260:Female; D005264:Femoral Fractures / Q000188:drug therapy* / Q000378:metabolism*; D005269:Femur / Q000187:drug effects / Q000503:physiopathology*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013324:Strontium / Q000008:administration & dosage*; D054457:Tissue Scaffolds; D016896:Treatment Outcome
chemical_list: D004343:Drug Implants; D011495:Histone-Lysine N-Methyltransferase; C000626228:Setd2 protein, rat; D013324:Strontium
keywords: Bone regeneration; H3K36me3; Osteoporosis; RNA-seq; Setd2; Sr-MBG