Stage-specific secretion of HMGB1 in cartilage regulates endochondral ossification.
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.
Taniguchi
Noboru
N
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Yoshida
Kenji
K
Ito
Tatsuo
T
Tsuda
Masanao
M
Mishima
Yasunori
Y
Furumatsu
Takayuki
T
Ronfani
Lorenza
L
Abeyama
Kazuhiro
K
Kawahara
Ko-ichi
K
Komiya
Setsuro
S
Maruyama
Ikuro
I
Lotz
Martin
M
Bianchi
Marco E
ME
Asahara
Hiroshi
H
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
D015415:Biomarkers; D002630:Chemotactic Factors; D024243:HMGB1 Protein