BBB Seminar: Attila Aszodi
The role of β1 integrins in skeletal development: lessons from knockout mice
Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany
Interactions of cells with the extracellular matrix (ECM) are pivotal for embryonic development, tissue homeostasis and repair. Integrins are transmembrane glycoproteins composed of non-covalently bound α and β subunits that act as receptors for ECM proteins and modulate cellular events involved in migration, proliferation, survival and differentiation. β1 integrin-containing heterodimers are highly expressed on skeletal cell types such as chondrocytes and osteoblasts implicating their role in skeletogenesis. Most skeletal elements that form via cartilaginous intermediates in the process of endochondral ossification exhibit two highly organized structures: the columnar growth plate (GP), which drives the proximodistal (PD) elongation of the bones and the articular cartilage (AC), which provides low-friction, shock absorbing diarthrodial joint surfaces. Disturbance of GP morphogenesis is frequently associated with skeletal dysplasias, while the imbalance of AC metabolism leads to osteoarthritis (OA), a progressive degenerative disorder of the synovial joints.
To explore the in vivo functions of β1 integrins in skeletal development and diseases we have generated mouse strains in which the β1 integrin gene (Itgb1) was conditionally deleted by cre-loxp-mediated transgenesis. Chondrocyte-specific deletion of Itgb1 leads to severe chondrodysplasia and a high mortality rate at birth associated with proliferation, cytokinesis and polarity defects of GP chondrocytes. In the proliferative zone (PZ) of normal GP, the cells are flattened and oriented along the mediolateral (ML) axis of the GP. Mitotic figures in the elongated chondrocytes lie perpendicular to the PD direction of growth, while cell divisions occur parallel to the columns followed by a gliding movement of the daughter cells. β1 integrin-deficiency results in chondrocyte rounding and lack of GP columns. Based on results from in vivo and in vitro experiments, we propose that b1 integrins provide adhesive cues for chondrocyte geometry, which in turn orients the mitotic spindle and determines the division axis, and for chondrocyte intercalation to shape the three-dimensional structure of the GP.
To assess the impact of β1 integrin-mediated cell-matrix interactions on the function of knee joints, we ablated Itgb1 in mesenchymal precursor cells of the embryonic limb-bud. The analyses of mutant mice show that 1) the lack of β1 integrins has no obvious impact on AC cartilage homeostasis; 2) β1 integrins are essential for proper development and structural organization of joint tissues; 3) structural changes lead to a softer AC surface and 4) softening of the AC increases OA severity only upon mechanical loading. Taken together, these observations suggest that β1 integrin signaling is not a good candidate for intervention in osteoarthritis.
Host: Donald Gullberg , Department of Biomedicine