title: FFAs-ROS-ERK/P38 pathway plays a key role in adipocyte lipotoxicity on osteoblasts in co-culture.
abstract: The accumulation of adipocytes in bone marrow is common in a variety of pathophysiological conditions, including obesity, insulin resistance, type 2 diabetes, and aging. Adipocytes in bone marrow exhibit severe adverse effect on osteoblast differentiation, proliferation, and function. However, the molecular mechanism of adipocytes lipotoxicity on osteoblasts is still far from completely understood. The present study was designed to investigate the signaling pathway responsible for adipocytes lipotoxicity on osteoblasts. Using a co-culture system, we have identified that free fatty acids (FFAs) released by the adipocytes inhibited osteoblasts proliferation and function and induced osteoblasts apoptosis, evidenced by decreased cell viability/proliferation, ALP activity, expression of runt-related transcription factor 2 (RunX2), type I collagen (ColA1) and osteocalcin and alizarin red staining. Dexamethasone (Dex) promoted the inhibitory effect of adipocytes on osteoblasts through stimulating FFAs release. Dex-exacerbated FFAs release from adipocytes contributes to reactive oxygen species (ROS) production. In the co-culture system, the phosphorylation of extracellular signal-regulated kinase (ERK)/P38 was increased and inhibition of ERK/P38 significantly suppressed adipocytes lipotoxicity. FFAs-generated ROS was responsible for adipocytes-induced activation of ERK/P38 signaling. In conclusion, FFAs-ROS-ERK/P38 pathway plays a key role in adipocyte lipotoxicity on osteoblasts in co-culture. The evidence provides new insights into the mechanisms underlying the lipotoxic effect of adipocytes on bone within the marrow microenvironment and prevention of lipotoxicity on bone metabolism.
authors.affiliation: Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, 15 Changle West Road, Xi'an, Shaanxi 710032, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Dong
authors.affiliation: Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, 15 Changle West Road, Xi'an, Shaanxi 710032, People's Republic of China.
authors.forename: Long
authors.initials: L
authors.lastname: Bi
authors.affiliation: Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, 15 Changle West Road, Xi'an, Shaanxi 710032, People's Republic of China.
authors.forename: Shu
authors.initials: S
authors.lastname: He
authors.affiliation: Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, 15 Changle West Road, Xi'an, Shaanxi 710032, People's Republic of China.
authors.forename: Guolin
authors.initials: G
authors.lastname: Meng
authors.affiliation: Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, 15 Changle West Road, Xi'an, Shaanxi 710032, People's Republic of China.
authors.forename: Boyuan
authors.initials: B
authors.lastname: Wei
authors.affiliation: Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, 15 Changle West Road, Xi'an, Shaanxi 710032, People's Republic of China.
authors.forename: Shuaijun
authors.initials: S
authors.lastname: Jia
authors.affiliation: Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, 15 Changle West Road, Xi'an, Shaanxi 710032, People's Republic of China. Electronic address: ljreny@fmmu.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D018920:Coculture Techniques; D003907:Dexamethasone / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000502:physiology*; D050356:Lipid Metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D005230:Fatty Acids, Nonesterified; D017382:Reactive Oxygen Species; D003907:Dexamethasone; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Adipocyte; Extracellular signal-regulated kinase; Free fatty acids; Lipotoxicity; Osteoblast; P38; Reactive oxygen species