The metalloproteinase MT1-MMP is required for normal development and maintenance of osteocyte processes in bone

Abstract

The osteocyte is the terminally differentiated state of the osteogenic mesenchymal progenitor immobilized in the bone matrix. Despite their numerical prominence, little is known about osteocytes and their formation. Osteocytes are physically separated in the bone matrix but seemingly compensate for their seclusion from other cells by maintaining an elaborate network of cell processes through which they interact with other osteocytes and bone-lining cells at the periosteal and endosteal surfaces of the bone. This highly organized architecture suggests that osteocytes make an active contribution to the structure and maintenance of their environment rather than passively submitting to random embedding during bone growth or repair. The most abundant matrix protein in the osteocyte environment is type-I collagen and we demonstrate here that, in the mouse, osteocyte phenotype and the formation of osteocyte processes is highly dependent on continuous cleavage of type-I collagen. This collagenolytic activity and formation of osteocyte processes is dependent on matrix metalloproteinase activity. Specifically, a deficiency of membrane type-1 matrix metalloproteinase leads to disruption of collagen cleavage in osteocytes and ultimately to the loss of formation of osteocyte processes. Osteocytogenesis is thus an active invasive process requiring cleavage of collagen for maintenance of the osteocyte phenotype.

E11/gp38 Selective Expression in Osteocytes: Regulation by Mechanical Strain and Role in Dendrite Elongation

“…Okada and colleagues documented an increase in canaliculi in rats between 3 and 12 weeks of age (33). Holmbeck and colleagues (18) have obtained similar results with mice and have shown osteocytogenesis to be an active, invasive process requiring cleavage of collagen and other matrix molecules by MT1-MMP. They propose that MT1-MMP is necessary for the formation of canaliculi as osteocytes in MT1-MMP-null mice have a significantly reduced number and length of dendritic processes.…”

Glucocorticoid-dependent Wnt signaling by mature osteoblasts is a key regulator of cranial skeletal development in mice

“…This cartilage then grows substantially during the later part of embryogenesis and the early neonatal period, but 433 RESEARCH ARTICLE Regulation of cranial bone development gradually disappears as ossification proceeds concurrent with the degradation of the extracellular matrix of cartilage and chondrocyte apoptosis. This process is arrested in Mmp14-deficient mice (Holmbeck et al, 1999;Holmbeck et al, 2003;Holmbeck et al, 2005). As Mmp14 is a type I membrane-bound protein, it needs to be expressed by resident chondrocytes to catalyse cartilage degradation.…”

Complementary Roles of Intracellular and Pericellular Collagen Degradation Pathways In Vivo

“…Postnatal death caused by combined deficits in intracellular and pericellular collagen degradation pathways. Because of the engagement of both uPARAP/Endo180 and MT1-MMP in collagen turnover, the conspicuous similarity of the expression patterns of the two molecules in bone-forming tissue (see above) (19)(20)(21)45), the fundamentally different mechanisms of collagen turnover (intracellular versus pericellular), and the marked accumulation of intracellular collagen in bone-forming cells of MϪ mice (2,19), we hypothesized that the collagen turnover pathways defined by the two molecules could act in a complementary manner within the bone microenvironment. If this was true, combined uPARAP/Endo180 and MT1-MMP deficiencies would be predicted to have a more severe effect on bone formation than an individual deficiency in either uPARAP/Endo180 or MT1-MMP.…”