title: Clock Gene Bmal1 Modulates Human Cartilage Gene Expression by Crosstalk With Sirt1.
abstract: The critical regulation of the peripheral circadian gene implicated in osteoarthritis (OA) has been recently recognized; however, the causative role and clinical potential of the peripheral circadian rhythm attributable to such effects remain elusive. The purpose of this study was to elucidate the role of a circadian gene Bmal1 in human cartilage and pathophysiology of osteoarthritis. In our present study, the mRNA and protein levels of circadian rhythm genes, including nicotinamide adenine dinucleotide oxidase (NAD(+)) and sirtuin 1 (Sirt1), in human knee articular cartilage were determined. In OA cartilage, the levels of both Bmal1 and NAD(+) decreased significantly, which resulted in the inhibition of nicotinamide phosphoribosyltransferase activity and Sirt1 expression. Furthermore, the knockdown of Bmal1 was sufficient to decrease the level of NAD(+) and aggravate OA-like gene expression changes under the stimulation of IL-1β. The overexpression of Bmal1 relieved the alteration induced by IL-1β, which was consistent with the effect of the inhibition of Rev-Erbα (known as NR1D1, nuclear receptor subfamily 1, group D). On the other hand, the transfection of Sirt1 small interfering RNA not only resulted in a reduction of the protein expression of Bmal1 and a moderate increase of period 2 (per2) and Rev-Erbα but also further exacerbated the survival of cells and the expression of cartilage matrix-degrading enzymes induced by IL-1β. Overexpression of Sirt1 restored the metabolic imbalance of chondrocytes caused by IL-1β. These observations suggest that Bmal1 is a key clock gene to involve in cartilage homeostasis mediated through sirt1 and that manipulating circadian rhythm gene expression implicates an innovative strategy to develop novel therapeutic agents against cartilage diseases.
authors.affiliation: Center for Translational Medicine (W.Y., X.K., X.J., Z.Q., T.X., N.Q., D.F., W.P., Q.C., S.W.), the First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, People's Republic of China; Key Laboratory of Environment and Genes Related to Diseases (J.L., H.L., Z.M., H.S.), Ministry of Education, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Hong Hui Hospital (D.F., W.P.), Xi'an Jiaotong University School of Medicine, and Frontier Institute of Science and Technology (Q.C.), Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Department of Pharmacy (N.Q.), Luoyang Orthopedic Hospital, Luoyang, 450052 Henan, China; and Department of Orthopaedics (Q.C.), Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Center for Translational Medicine (W.Y., X.K., X.J., Z.Q., T.X., N.Q., D.F., W.P., Q.C., S.W.), the First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, People's Republic of China; Key Laboratory of Environment and Genes Related to Diseases (J.L., H.L., Z.M., H.S.), Ministry of Education, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Hong Hui Hospital (D.F., W.P.), Xi'an Jiaotong University School of Medicine, and Frontier Institute of Science and Technology (Q.C.), Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Department of Pharmacy (N.Q.), Luoyang Orthopedic Hospital, Luoyang, 450052 Henan, China; and Department of Orthopaedics (Q.C.), Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Kang
authors.affiliation: Center for Translational Medicine (W.Y., X.K., X.J., Z.Q., T.X., N.Q., D.F., W.P., Q.C., S.W.), the First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, People's Republic of China; Key Laboratory of Environment and Genes Related to Diseases (J.L., H.L., Z.M., H.S.), Ministry of Education, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Hong Hui Hospital (D.F., W.P.), Xi'an Jiaotong University School of Medicine, and Frontier Institute of Science and Technology (Q.C.), Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Department of Pharmacy (N.Q.), Luoyang Orthopedic Hospital, Luoyang, 450052 Henan, China; and Department of Orthopaedics (Q.C.), Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Jiali
authors.initials: J
authors.lastname: Liu
authors.affiliation: Center for Translational Medicine (W.Y., X.K., X.J., Z.Q., T.X., N.Q., D.F., W.P., Q.C., S.W.), the First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, People's Republic of China; Key Laboratory of Environment and Genes Related to Diseases (J.L., H.L., Z.M., H.S.), Ministry of Education, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Hong Hui Hospital (D.F., W.P.), Xi'an Jiaotong University School of Medicine, and Frontier Institute of Science and Technology (Q.C.), Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Department of Pharmacy (N.Q.), Luoyang Orthopedic Hospital, Luoyang, 450052 Henan, China; and Department of Orthopaedics (Q.C.), Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Huixia
authors.initials: H
authors.lastname: Li
authors.affiliation: Center for Translational Medicine (W.Y., X.K., X.J., Z.Q., T.X., N.Q., D.F., W.P., Q.C., S.W.), the First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, People's Republic of China; Key Laboratory of Environment and Genes Related to Diseases (J.L., H.L., Z.M., H.S.), Ministry of Education, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Hong Hui Hospital (D.F., W.P.), Xi'an Jiaotong University School of Medicine, and Frontier Institute of Science and Technology (Q.C.), Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Department of Pharmacy (N.Q.), Luoyang Orthopedic Hospital, Luoyang, 450052 Henan, China; and Department of Orthopaedics (Q.C.), Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Zhengmin
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Center for Translational Medicine (W.Y., X.K., X.J., Z.Q., T.X., N.Q., D.F., W.P., Q.C., S.W.), the First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, People's Republic of China; Key Laboratory of Environment and Genes Related to Diseases (J.L., H.L., Z.M., H.S.), Ministry of Education, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Hong Hui Hospital (D.F., W.P.), Xi'an Jiaotong University School of Medicine, and Frontier Institute of Science and Technology (Q.C.), Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Department of Pharmacy (N.Q.), Luoyang Orthopedic Hospital, Luoyang, 450052 Henan, China; and Department of Orthopaedics (Q.C.), Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Jin
authors.affiliation: Center for Translational Medicine (W.Y., X.K., X.J., Z.Q., T.X., N.Q., D.F., W.P., Q.C., S.W.), the First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, People's Republic of China; Key Laboratory of Environment and Genes Related to Diseases (J.L., H.L., Z.M., H.S.), Ministry of Education, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Hong Hui Hospital (D.F., W.P.), Xi'an Jiaotong University School of Medicine, and Frontier Institute of Science and Technology (Q.C.), Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Department of Pharmacy (N.Q.), Luoyang Orthopedic Hospital, Luoyang, 450052 Henan, China; and Department of Orthopaedics (Q.C.), Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Qian
authors.affiliation: Center for Translational Medicine (W.Y., X.K., X.J., Z.Q., T.X., N.Q., D.F., W.P., Q.C., S.W.), the First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, People's Republic of China; Key Laboratory of Environment and Genes Related to Diseases (J.L., H.L., Z.M., H.S.), Ministry of Education, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Hong Hui Hospital (D.F., W.P.), Xi'an Jiaotong University School of Medicine, and Frontier Institute of Science and Technology (Q.C.), Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Department of Pharmacy (N.Q.), Luoyang Orthopedic Hospital, Luoyang, 450052 Henan, China; and Department of Orthopaedics (Q.C.), Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Tianping
authors.initials: T
authors.lastname: Xie
authors.affiliation: Center for Translational Medicine (W.Y., X.K., X.J., Z.Q., T.X., N.Q., D.F., W.P., Q.C., S.W.), the First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, People's Republic of China; Key Laboratory of Environment and Genes Related to Diseases (J.L., H.L., Z.M., H.S.), Ministry of Education, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Hong Hui Hospital (D.F., W.P.), Xi'an Jiaotong University School of Medicine, and Frontier Institute of Science and Technology (Q.C.), Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Department of Pharmacy (N.Q.), Luoyang Orthopedic Hospital, Luoyang, 450052 Henan, China; and Department of Orthopaedics (Q.C.), Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Na
authors.initials: N
authors.lastname: Qin
authors.affiliation: Center for Translational Medicine (W.Y., X.K., X.J., Z.Q., T.X., N.Q., D.F., W.P., Q.C., S.W.), the First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, People's Republic of China; Key Laboratory of Environment and Genes Related to Diseases (J.L., H.L., Z.M., H.S.), Ministry of Education, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Hong Hui Hospital (D.F., W.P.), Xi'an Jiaotong University School of Medicine, and Frontier Institute of Science and Technology (Q.C.), Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Department of Pharmacy (N.Q.), Luoyang Orthopedic Hospital, Luoyang, 450052 Henan, China; and Department of Orthopaedics (Q.C.), Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Dongxu
authors.initials: D
authors.lastname: Feng
authors.affiliation: Center for Translational Medicine (W.Y., X.K., X.J., Z.Q., T.X., N.Q., D.F., W.P., Q.C., S.W.), the First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, People's Republic of China; Key Laboratory of Environment and Genes Related to Diseases (J.L., H.L., Z.M., H.S.), Ministry of Education, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Hong Hui Hospital (D.F., W.P.), Xi'an Jiaotong University School of Medicine, and Frontier Institute of Science and Technology (Q.C.), Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Department of Pharmacy (N.Q.), Luoyang Orthopedic Hospital, Luoyang, 450052 Henan, China; and Department of Orthopaedics (Q.C.), Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Pan
authors.affiliation: Center for Translational Medicine (W.Y., X.K., X.J., Z.Q., T.X., N.Q., D.F., W.P., Q.C., S.W.), the First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, People's Republic of China; Key Laboratory of Environment and Genes Related to Diseases (J.L., H.L., Z.M., H.S.), Ministry of Education, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Hong Hui Hospital (D.F., W.P.), Xi'an Jiaotong University School of Medicine, and Frontier Institute of Science and Technology (Q.C.), Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Department of Pharmacy (N.Q.), Luoyang Orthopedic Hospital, Luoyang, 450052 Henan, China; and Department of Orthopaedics (Q.C.), Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Center for Translational Medicine (W.Y., X.K., X.J., Z.Q., T.X., N.Q., D.F., W.P., Q.C., S.W.), the First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, People's Republic of China; Key Laboratory of Environment and Genes Related to Diseases (J.L., H.L., Z.M., H.S.), Ministry of Education, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Hong Hui Hospital (D.F., W.P.), Xi'an Jiaotong University School of Medicine, and Frontier Institute of Science and Technology (Q.C.), Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Department of Pharmacy (N.Q.), Luoyang Orthopedic Hospital, Luoyang, 450052 Henan, China; and Department of Orthopaedics (Q.C.), Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Sun
authors.affiliation: Center for Translational Medicine (W.Y., X.K., X.J., Z.Q., T.X., N.Q., D.F., W.P., Q.C., S.W.), the First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, People's Republic of China; Key Laboratory of Environment and Genes Related to Diseases (J.L., H.L., Z.M., H.S.), Ministry of Education, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Hong Hui Hospital (D.F., W.P.), Xi'an Jiaotong University School of Medicine, and Frontier Institute of Science and Technology (Q.C.), Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Department of Pharmacy (N.Q.), Luoyang Orthopedic Hospital, Luoyang, 450052 Henan, China; and Department of Orthopaedics (Q.C.), Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Shufang
authors.initials: S
authors.lastname: Wu
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000502:physiology*; D056926:CLOCK Proteins / Q000502:physiology; D002356:Cartilage / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008875:Middle Aged; D056564:Sirtuin 1 / Q000502:physiology*
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; D056926:CLOCK Proteins; C447939:SIRT1 protein, human; D056564:Sirtuin 1