title: Stage-specific secretion of HMGB1 in cartilage regulates endochondral ossification.
abstract: High mobility group box 1 protein (HMGB1) is a chromatin protein that has a dual function as a nuclear factor and as an extracellular factor. Extracellular HMGB1 released by damaged cells acts as a chemoattractant, as well as a proinflammatory cytokine, suggesting that HMGB1 is tightly connected to the process of tissue organization. However, the role of HMGB1 in bone and cartilage that undergo remodeling during embryogenesis, tissue repair, and disease is largely unknown. We show here that the stage-specific secretion of HMGB1 in cartilage regulates endochondral ossification. We analyzed the skeletal development of Hmgb1(-/-) mice during embryogenesis and found that endochondral ossification is significantly impaired due to the delay of cartilage invasion by osteoclasts, osteoblasts, and blood vessels. Immunohistochemical analysis revealed that HMGB1 protein accumulated in the cytosol of hypertrophic chondrocytes at growth plates, and its extracellular release from the chondrocytes was verified by organ culture. Furthermore, we demonstrated that the chondrocyte-secreted HMGB1 functions as a chemoattractant for osteoclasts and osteoblasts, as well as for endothelial cells, further supporting the conclusion that Hmgb1(-/-) mice are defective in cell invasion. Collectively, these findings suggest that HMGB1 released from differentiating chondrocytes acts, at least in part, as a regulator of endochondral ossification during osteogenesis.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Noboru
authors.initials: N
authors.lastname: Taniguchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Yoshida
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Ito
authors.forename: Masanao
authors.initials: M
authors.lastname: Tsuda
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Mishima
authors.forename: Takayuki
authors.initials: T
authors.lastname: Furumatsu
authors.forename: Lorenza
authors.initials: L
authors.lastname: Ronfani
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Abeyama
authors.forename: Ko-ichi
authors.initials: K
authors.lastname: Kawahara
authors.forename: Setsuro
authors.initials: S
authors.lastname: Komiya
authors.forename: Ikuro
authors.initials: I
authors.lastname: Maruyama
authors.forename: Martin
authors.initials: M
authors.lastname: Lotz
authors.forename: Marco E
authors.initials: ME
authors.lastname: Bianchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asahara
mesh_terms: D000818:Animals; D015415:Biomarkers; D001842:Bone and Bones / Q000002:abnormalities / Q000098:blood supply / Q000196:embryology; D002356:Cartilage / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D002630:Chemotactic Factors / Q000378:metabolism; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D004622:Embryo, Mammalian / Q000002:abnormalities; D006132:Growth Plate / Q000166:cytology / Q000378:metabolism; D024243:HMGB1 Protein / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis
chemical_list: D015415:Biomarkers; D002630:Chemotactic Factors; D024243:HMGB1 Protein