Lectin-like oxidized low-density lipoprotein receptor-1 abrogation causes resistance to inflammatory bone destruction in mice, despite promoting osteoclastogenesis in the steady state.
Inflammatory bone diseases have been attributed to increased bone resorption by augmented and activated bone-resorbing osteoclasts in response to inflammation. Although the production of diverse proinflammatory cytokines is induced at the inflamed sites, the inflammation also generates reactive oxygen species that modify many biological compounds, including lipids. Among the oxidized low-density lipoprotein (LDL) receptors, lectin-like oxidized LDL receptor-1 (LOX-1), which is a key molecule in the pathogenesis of multifactorial inflammatory atherosclerosis, was downregulated with osteoclast differentiation. Here, we demonstrate that LOX-1 negatively regulates osteoclast differentiation by basically suppressing the cell-cell fusion of preosteoclasts. The LOX-1-deleted (LOX-1(-/-)) mice consistently decreased the trabecular bone mass because of elevated bone resorption during the growing phase. In contrast, when the calvaria was inflamed by a local lipopolysaccharide-injection, the inflammation-induced bone destruction accompanied by the elevated expression of osteoclastogenesis-related genes was reduced by LOX-1 deficiency. Moreover, the expression of receptor activator of NF-κB ligand (RANKL), a trigger molecule for osteoclast differentiation, evoked by the inflammation was also abrogated in the LOX-1(-/-) mice. Osteoblasts, the major producers of RANKL, also expressed LOX-1 in response to proinflammatory agents, interleukin-1β and prostaglandin E2. In the co-culture of LOX-1(-/-) osteoblasts and wild-type osteoclast precursors, the osteoclastogenesis induced by interleukin-1β and prostaglandin E2 decreased; this process occurred in parallel with the downregulation of osteoblastic RANKL expression. Collectively, LOX-1 abrogation results in resistance to inflammatory bone destruction, despite promoting osteoclastogenesis in the steady state. Our findings indicate the novel involvement of LOX-1 in physiological bone homeostasis and inflammatory bone diseases.
Division of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-0283, Japan; Division of Orthodontics, Meikai University School of Dentistry, Sakado, Saitama 350-0283, Japan.
Mai
M
Nakayachi
Division of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-0283, Japan. Electronic address: junta.ito@dent.meikai.ac.jp.
Junta
J
Ito
Division of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-0283, Japan.
Chiyomi
C
Hayashida
Division of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-0283, Japan; Division of Oral and Maxillofacial Surgery, Meikai University School of Dentistry, Sakado, Saitama 350-0283, Japan.
Yoko
Y
Ohyama
Department of Vascular Physiology, National Cerebral and Cardiovascular Center, Suita, Osaka 565-8565, Japan.
Akemi
A
Kakino
Division of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-0283, Japan; Division of Oral-maxillofacial Surgery, Dentistry and Orthodontics, The University of Tokyo Hospital, Hongo, Tokyo 113-8655, Japan.
Mari
M
Okayasu
Division of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-0283, Japan.
Takuya
T
Sato
Division of Oral-maxillofacial Surgery, Dentistry and Orthodontics, The University of Tokyo Hospital, Hongo, Tokyo 113-8655, Japan.
Toru
T
Ogasawara
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara, Tokyo 142-8501, Japan.
Toshio
T
Kaneda
Division of Orthodontics, Meikai University School of Dentistry, Sakado, Saitama 350-0283, Japan.
Naoto
N
Suda
Department of Vascular Physiology, National Cerebral and Cardiovascular Center, Suita, Osaka 565-8565, Japan; Department of Physiology, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.
Tatsuya
T
Sawamura
Division of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-0283, Japan. Electronic address: y-hakeda@dent.meikai.ac.jp.
Yoshiyuki
Y
Hakeda
D000818:Animals; D015153:Blotting, Western; D001847:Bone Diseases / Q000378:metabolism* / Q000473:pathology; D001862:Bone Resorption / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D051127:Scavenger Receptors, Class E / Q000378:metabolism*
C495138:Olr1 protein, mouse; D051127:Scavenger Receptors, Class E
Inflammatory bone destruction; Lectin-like oxidized low-density lipoprotein receptor-1; Osteoblasts; Osteoclastogenesis; Osteoclasts