β1 integrins regulate chondrocyte rotation, G1 progression, and cytokinesis

Abstract

␤1 integrins are highly expressed on chondrocytes, where they mediate adhesion to cartilage matrix proteins. To assess the functions of ␤1 integrin during skeletogenesis, we inactivated the ␤1 integrin gene in chondrocytes. We show here that these mutant mice develop a chondrodysplasia of various severity. ␤1-deficient chondrocytes had an abnormal shape and failed to arrange into columns in the growth plate. This is caused by a lack of motility, which is in turn caused by a loss of adhesion to collagen type II, reduced binding to and impaired spreading on fibronectin, and an abnormal F-actin organization. In addition, mutant chondrocytes show decreased proliferation caused by a defect in G1/S transition and cytokinesis. The G1/S defect is, at least partially, caused by overexpression of Fgfr3, nuclear translocation of Stat1/Stat5a, and up-regulation of the cell cycle inhibitors p16 and p21. Altogether these findings establish that ␤1-integrin-dependent motility and proliferation of chondrocytes are mandatory events for endochondral bone formation to occur.[Keywords: Integrin; fibronectin; endochondral ossification; growth plate; cytokinesis; FGF] Supplemental material is available at http://www.genesdev.org.

Collagens in the progression and complications of atherosclerosis

“…This finding also implies that type I and type II collagens, which seem to promote mineralization, are unlikely to use the α 1 β 1 receptor to mediate these effects, but rather, they may utilize other integrin combinations, such as α 2 β 1 , α 10 β 1 or the DDRs. In favor of this generalization, deficiencies in α 10 , β 1 , or DDR2 have been shown to hinder chondrocyte maturation and matrix mineralization in calcifying bones, [147][148][149] although it is not known whether similar mechanisms are at play in vascular calcification.…”

Primary cilia organization reflects polarity in the growth plate and implies loss of polarity and mosaicism in osteochondroma

“…34 Movement/rotation problems in the chondrocytes of the growth plate have been reported in b1-integrin-null mice. 33 The b1-integrin-null growth plates show larger and round-shaped proliferating chondrocytes arranged side by side, possibly reflecting impaired movement and inability to form columns. 33 Strikingly, b1-integrin receptors have been reported to colocalize with a-tubulin in the primary cilia of chondrocytes.…”

“…33 The b1-integrin-null growth plates show larger and round-shaped proliferating chondrocytes arranged side by side, possibly reflecting impaired movement and inability to form columns. 33 Strikingly, b1-integrin receptors have been reported to colocalize with a-tubulin in the primary cilia of chondrocytes. 35 The loss of EXT expression results in disordered distribution of heparan sulfate proteoglycans.…”

“…2,4,33 Integrins are the major class of cell adhesion molecules that mediate cellmatrix signaling pathways. 33 Integrins have heparan-binding domains, which indicate that heparan sulfate proteoglycans may modulate integrin signaling and cell adhesion. 34 Movement/rotation problems in the chondrocytes of the growth plate have been reported in b1-integrin-null mice.…”

Epiphyseal growth plate and secondary peripheral chondrosarcoma: the neighbours matter

“…Integrins regulate centrosome function, the assembly of the mitotic spindle and cytokinesis [11]. In β1-null growth plates, chondrocytes display mitotic figures perpendicular to the long axis, but they stay side-by-side and failed to move over each other and form columns, suggesting that β1 integrins regulate chondrocyte shape and rotation [12]. In the hypertrophic zone, chondrocytes stop proliferating and change their expression profile to synthesize type X collagen and to prepare for mineralization of the surrounding cartilaginous ECM (Figure 1) [6].…”