Cartilage and bone require the production of specific types of extracellular matrices. The properties of these matrices are largely determined by the major macromolecules of the tissue, collagen and proteoglycan. These macromolecules are necessary for the tensile strength and resiliency, respectively, of these tissues. Deficiencies, abnormal production, or a change in the genetic type of these macromolecules are associated with osteoarthrosis, rheumatoid arthritis, diabetes, and inherited connective tissue abnormalities such as the Ehlers-Danlos Syndromes and the osteochondrodysplasias. Very little is known about the specific biochemical defects that underlie these diseases. The formation of an extracellular matrix requires a complex expression of genes which code for specific matrix components. During embryonic development of endochondral bone, there are distinct spacial and temporal transitions of collagen and proteoglycan types. Many skeletal dysplasias have abnormal growth plate organization and matrix architecture. This suggests that, during development, defects in synthesis, release, or assembly of connective tissue macromolecules are involved in these diseases. Consequently, investigation of the regulation of bone development at the level of gene expression should yield information which will be relevent to the understanding and, eventually, the treatment of skeletal dysplasias. The focus of the present studies is on the proteoglycan component of the extracellular matrix. In the extracellular matrix proteoglycans exist in large aggregates attached to hyaluronic acid. The proteoglycan monomer consists of a core protein which is extensively modified by the addition of chondroitin sulfate glycosaminoglycans. A second protein, the link protein, is involved in the aggregate and serves to stabilize the association of the proteoglycan monomer with the hyaluronic acid. Our investigations will concentrate on the biosynthesis and regulation of production of the core and link proteins of the proteoglycan aggregate. The approach taken will be to develop DNA hybridization probes which will be used to trace mRNA levels in model systems of proteoglycan biosynthesis and endochondral bone development.
