title: High glucose-induced LIF suppresses osteoblast differentiation via regulating STAT3/SOCS3 signaling.
abstract: High glucose (HG) is conceived to regulate bone metabolism in patients with diabetic mellitus (DM). In the present study, we examined the level of leukemia inhibitory factor (LIF), a pleiotropic cytokine in interleukin (IL)-6 family, in T2DM patients and investigated the regulation by HG on the induction of LIF/signal transducer and activator of transcription 3 (STAT3) signaling. Then we determined the regulation of HG and LIF on the osteoblast differentiation via measuring the ALP activity, matrix mineralization, and the expression of alkaline phosphatase (ALP), Runt-related transcription factor 2 (RUNX2), Osteocalcin (OCN) and osteopontin (OPN) in human osteoblast MG-63 cells. In addition, we evaluated the dependence of suppressor of cytokine signaling 3 (SOCS3)/STAT3 signaling in the progress. Results indicated significantly higher serum levels of high-sensitivity C-reactive protein (hsCRP), IL-1β, IL-6 and LIF in T2DM patients. HG induced markedly higher levels of these cytokines in vitro. Furthermore, either HG or LIF reduced the expression of ALP, OCN and RUNX2 in both mRNA and protein levels. In addition, LIF markedly promoted the expression of SOCS3, significantly upregulated the phosphorylation of STAT3 in MG-63 cells; and the downregulation of the four osteogenic differentiation-associated markers were restored by 50 or 100nM STAT3 inhibitor, JSI-124. In summary, this study has shown that LIF is implicated in the HG-mediated inhibition of osteoblast differentiation, via promoting STAT3/SOCS3 signaling. This study may provide insights into the signal pathway of HG-induced bone loss or delayed injured joint healing.
authors.affiliation: Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China.
authors.forename: Changlu
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China. Electronic address: dianm_jiang@126.com.
authors.forename: Dianming
authors.initials: D
authors.lastname: Jiang
mesh_terms: D002454:Cell Differentiation; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism*
chemical_list: C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D005947:Glucose
keywords: High glucose; LIF; Osteoblast differentiation; STAT3/SOCS3 signaling