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 42days 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.
Highlights
Adhesion of cells to extracellular matrices is of fundamental importance for a wide range of cellular functions, including cell differentiation, proliferation, and survival [1]
Supportive of a potential involvement of integrins in the effect of AMBN on mineralized tissue homeostasis, our study revealed that the AMBN-induced increase in osteoclast count was significantly reduced when antibodies against integrin α2β1 or an inhibitor against extracellular-signalregulated kinases (ERK)-1 were applied to the culture medium
Albeit first introduced as a protein of the developing enamel matrix, there is increasing evidence that the secretory calcium-binding phosphoprotein (SCPP) family member AMBN is localized in other tissues such as bone, where it plays significant roles associated with mineral metabolism
Summary
Adhesion of cells to extracellular matrices is of fundamental importance for a wide range of cellular functions, including cell differentiation, proliferation, and survival [1]. Among many cell types in which surface adhesion plays a critical role, osteoclasts are arguably some of the most prominent, likely because of the necessity of osteoclast precursors, i.e. circulatory hematopoietic monocytes/macrophages, to attach to specific resorption sites and further differentiate, and because of the proximity of osteoclasts to bone as a requirement for leakage-free delivery of acids and proteases to enable targeted bone resorption [2]. Osteoclast surface attachment is a first and essential step in a cascade of events that continues with osteoclast polarization, formation of podosomes and a sealing zone, and secretion of acids and proteases for the resorption of bone. The contact of osteoclasts with the apatitic bone surface activates small GTPases of the Rho family [3,4], which in turn induces osteoclast spreading, podosome formation and the formation of the sealing zone [5,6,7]. The intricate balance between bone resorption and apposition is exemplified during physiological tooth movement where bone resorption at movementdirection alveolar bone walls and bone apposition on the contralateral side plays a role in the continuous maintenance of the attachment apparatus
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