title: Progranulin plays crucial roles in preserving bone mass by inhibiting TNF-α-induced osteoclastogenesis and promoting osteoblastic differentiation in mice.
abstract: A close correlation between atherosclerosis, inflammation, and osteoporosis has been recognized, although the precise mechanism remains unclear. The growth factor progranulin (PGRN) is expressed in various cells such as macrophages, leukocytes, and chondrocytes. PGRN plays critical roles in a variety of diseases, such as atherosclerosis and arthritis by inhibiting Tumor Necrosis Factor-α (TNF-α) signaling. The purpose of this study was to investigate the effect of PGRN on bone metabolism. Forty-eight-week old female homozygous PGRN knockout mice (PGRN-KO) (n = 8) demonstrated severe low bone mass in the distal femur compared to age- and sex-matched wild type C57BL/6J mice (WT) (n = 8) [BV/TV (%): 5.8 vs. 16.6; p < 0.001, trabecular number (1/mm): 1.6 vs. 3.8; p < 0.001]. In vitro, PGRN inhibited TNF-α-induced osteoclastogenesis from spleen cells of PGRN-KO mice. Moreover, PGRN significantly promoted ALP activity, osteoblast-related mRNA (ALP, osteocalcin) expression in a dose-dependent manner and up-regulated osteoblastic differentiation by down-regulating phosphorylation of ERK1/2 in mouse calvarial cells. In conclusion, PGRN may be a promising treatment target for both atherosclerosis and inflammation-related osteoporosis.
authors: Department of Orthopaedic Surgery, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Takaaki
authors: T
authors: Noguchi
authors: Department of Orthopaedic Surgery, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: k-ebina@umin.ac.jp.
authors: Kosuke
authors: K
authors: Ebina
authors: Department of Orthopaedic Surgery, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Makoto
authors: M
authors: Hirao
authors: Department of Cardiovascular Medicine, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Ryota
authors: R
authors: Kawase
authors: Department of Cardiovascular Medicine, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Dental Anesthesiology, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Tohru
authors: T
authors: Ohama
authors: Department of Cardiovascular Medicine, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Community Medicine, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Shizuya
authors: S
authors: Yamashita
authors: Department of Orthopaedic Surgery, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Tokimitsu
authors: T
authors: Morimoto
authors: Department of Orthopaedic Surgery, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Kota
authors: K
authors: Koizumi
authors: Department of Orthopaedic Surgery, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Kazuma
authors: K
authors: Kitaguchi
authors: Department of Orthopaedic Surgery, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Hozo
authors: H
authors: Matsuoka
authors: Department of Orthopaedic Surgery, Japan Community Health Care Organization, Osaka Hospital, 4-2-78 Fukushima Ward, Osaka 586-8521, Japan.
authors: Shoichi
authors: S
authors: Kaneshiro
authors: Department of Orthopaedic Surgery, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Hideki
authors: H
authors: Yoshikawa
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000378:metabolism*; D002454:Cell Differentiation; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000378:metabolism*; D000077155:Granulins; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis; D000077153:Progranulins; D011859:Radiography; D014409:Tumor Necrosis Factor-alpha
chemical_list: D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D014409:Tumor Necrosis Factor-alpha
keywords: Bone metabolism; ERK1/2; Osteoblast; Osteoclast; Progranulin; TNF-α