Ameloblastin modulates osteoclastogenesis through the integrin/ERK pathway

• Published in: Bone (New York, N.Y.) Vol. 54; no. 1; pp. 157 - 168
• Main Authors: Lu, Xuanyu, Ito, Yoshihiro, Atsawasuwan, Phimon, Dangaria, Smit, Yan, Xiulin, Wu, Tuojiang, Evans, Carla A, Luan, Xianghong
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.05.2013; Elsevier
• Subjects: Actin; Actins - metabolism; AKT protein; AMBN protein; Ameloblastin; Animals; Biological and medical sciences; Bone (trabecular); Bone marrow; Bone Marrow Cells - drug effects; Bone Marrow Cells - metabolism; Bone mass; Bone Resorption - metabolism; Bone Resorption - pathology; Cell adhesion; Cell Adhesion - drug effects; Cell Adhesion - genetics; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cementum; Dental Enamel Proteins - genetics; Dental Enamel Proteins - metabolism; Dentistry; Epithelium - drug effects; Epithelium - growth & development; Epithelium - metabolism; ERK 1/2; Extracellular matrix; Extracellular signal-regulated kinase; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Developmental - drug effects; Humans; Integrin; Integrin alpha2beta1 - metabolism; Integrins; Keratin-14 - metabolism; Mandibles; MAP Kinase Signaling System - drug effects; Mice; Mice, Transgenic; Molar - diagnostic imaging; Molar - growth & development; Molar - metabolism; Molar - ultrastructure; Monocytes - drug effects; Monocytes - metabolism; Orthopedics; Osteoclastogenesis; Osteoclasts; Osteoclasts - drug effects; Osteoclasts - enzymology; Osteoclasts - metabolism; Osteogenesis - drug effects; Osteogenesis - genetics; Periodontal Ligament - drug effects; Periodontal Ligament - growth & development; Periodontal Ligament - metabolism; Phosphorylation; Phosphorylation - drug effects; Polymerization; Proto-Oncogene Proteins c-akt - metabolism; Radiography; RANK Ligand - pharmacology; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal transduction; Teeth; Tooth Root - diagnostic imaging; Tooth Root - metabolism; Tooth Root - pathology; Tooth Root - ultrastructure; Up-Regulation - drug effects; Up-Regulation - genetics; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Ameloblastin; Osteoclasts; Extracellular matrix; ERK 1/2; Integrin; Morphology; Osteoclast
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2013.01.041

Abstract Proteins of the extracellular matrix often have multiple functions to facilitate complex tasks ranging from signaling to structural support. Here we have focused on the function of one of the matrix proteins expressed in bones and teeth, the matrix adhesion protein ameloblastin (AMBN). Transgenic mice with 5-fold elevated AMBN levels in mandibles suffered from root cementum resorption, delamination, and reduced alveolar bone thickness. AMBN gain of function also resulted in a significant reduction in trabecular bone volume and bone mass dentistry in 42 days postnatal mouse jaws. In an in vitro model of osteoclastogenesis, AMBN modulated osteoclast differentiation from bone marrow derived monocytes (BMMCs), and dramatically increased osteoclast numbers and resorption pits. Furthermore, AMBN more than doubled BMMC adhesion, accelerated cell spreading, and promoted podosome belt and actin ring formation. These effects were associated with elevated ERK1/2 and AKT phosphorylation as well as higher expression of osteoclast activation related genes. Blocking integrin α2β1 and ERK 1/2 pathways alleviated the effects of AMBN on osteoclast differentiation. Together, our data indicate that AMBN increases osteoclast number and differentiation as well as mineralized tissue resorption by regulating cell adhesion and actin cytoskeleton polymerization, initiating integrin-dependent extracellular matrix signaling cascades and enhancing osteoclastogenesis.