Mammalian Skeletogenesis and Extracellular Matrix. What can We Learn from Knockout Mice?

Abstract

ABSTRACT. Formation of the vertebrate skeleton and the proper functions of bony and cartilaginous elements are determined by extracellular, cell surface and intracellular molecules. Genetic and biochemical analyses of human heritable skeletal disorders as well as the generation of knockout mice provide useful tools to identify the key players of mammalian skeletogenesis. This review summarises our recent work with transgenic animals carrying ablated genes for cartilage extracellular matrix proteins. Some of these mice exhibit a lethal phenotype associated with severe skeletal defects (type II collagen-null, perlecan-null), whereas others show mild (type IX collagen-null) or no skeletal abnormalities (matrilin-1-null, fibromodulin-null, tenascin-C-null). The appropriate human genetic disorders are discussed and contrasted with the knockout mice phenotypes.Key words: skeletogenesis/extracellular matrix/skeletal disorders/knockout mice Development of the mammalian skeleton is a temporally and spatially coordinated process, which is initiated by the condensation and differentiation of mesenchymal progenitor cells. Progenitors from the neural crest generate the craniofacial skeleton, sklerotomal cells form most elements of the axial skeleton, and the lateral plate mesoderm gives rise to the appendicular skeleton. Bone can develop via two basic mechanisms: mesenchymal precursor cells either differentiate directly into bone matrix-producing osteoblasts (intramembranous ossification) or first form a cartilaginous intermediate which is subsequently replaced by bone (endochondral ossification). The first mechanism is responsible for the formation of the flat bones of the skull, much of the facial skeleton, a part of the clavicle, and the cortical bone shaft of the long bones. The second mechanism occurs during the development of other bones such as long bones of the legs, vertebrae and ribs.Skeletal morphogenesis is characterized by the expression of a special set of extracellular matrix proteins and is tightly regulated via transcription factors, signaling molecules, hormones and local growth factors (Erlebacher et al., 1995). Our knowledge of how these molecules and factors act on skeletogenesis continuously increases, which not only helps to understand the normal development of skeletal elements but also contributes to a better understanding of skeletal diseases. During the last two decades human genetics has successfully identified gene mutations for many hereditary skeletal disorders resulting in osteochondrodysplasias or altered bone homeostasis (reviewed by Olsen, 1997a, 1997b). Furthermore, the conventional and conditional gene targeting experiments in mice have opened a new window which allow us to clarify the role of a particular gene product in skeletal development. The establishment of transgenic mouse strains with defined genetic alterations can also provide animal models for human skeletal disorders and might help to develop therapeutic tools for the treatment of various diseases affecting the skeleton.In ...

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