Ameloblastin modulates osteoclastogenesis through the integrin/ERK pathway

作者：Lu Xuanyu; Ito Yoshihiro; Atsawasuwan Phimon; Dangaria Smit; Yan Xiulin; Wu Tuojiang; Evans Carla A; Luan Xianghong^*

来源：Bone, 2013, 54(1): 157-168.

DOI：10.1016/j.bone.2013.01.041

• Osteoclasts
• Extracellular matrix
• Ameloblastin
• Integrin
• ERK 1/2

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, AMEN 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 ART phosphorylation as well as higher expression of osteoclast activation related genes. Blocking integrin alpha 2 beta 1 and ERIC 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.

• 出版日期2013-5