Hyaluronan production by means of Has2 gene expression in chondrocytes is essential for long bone development.

Mice possessing no Has2 expression in chondrocytes died near birth and displayed abnormalities throughout their skeleton. By embryonic day 18.5, the long bones were short and wide, and possessed excessive mineralization within their diaphysis, with little evidence of diaphyseal bone modeling.

The role of hyaluronan produced by Has2 gene expression in development of the spine.

Study Design: Histologic analysis of spine development in cartilage-specific knockout mice.

Objective: To evaluate the role hyaluronan produced by hyaluronan synthase-2 (Has2) in spine development.

Summary Of Background Data: The Has2 gene is responsible for most hyaluronan production throughout the body, including the skeleton.

The IGF-I receptor can alter the matrix metalloproteinase repertoire of tumor cells through transcriptional regulation of PKC-{alpha}.

The IGF-I receptor (IGF-IR) was identified as a tumor progression factor, but its role in invasion and metastasis has been the subject of some controversy. Previously we reported that in murine lung carcinoma M-27 cells, overexpression of IGF-IR increased the synthesis and activation of matrix metalloproteinase (MMP)-2 via Akt/phosphatidylinositol 3-kinase signaling. In contrast, we show here that in these and other cells, IGF-IR overexpression reduced the constitutive and phorbol 12-myristate 13-acetate (PMA)-inducible expression of three protein kinase C (PKC)-regulated metalloproteinases, MMP-3, MMP-9, and MMP-13, in cultured cells as well as in vivo in sc tumors.

Neoepitopes reveal the features of type II collagen cleavage and the identity of a collagenase involved in the transformation of the epiphyses anlagen in development.

In long bone development, the evolution of the cartilaginous anlagen into a secondary ossification center is initiated by the formation of canals. The excavation to create the canals is achieved through lysis of the two major cartilage components, aggrecan, and the type II collagen (COL2) fibril. The present study examines the lysis of the fibril.

Biogenesis of extracellular microfibrils: Multimerization of the fibrillin-1 C terminus into bead-like structures enables self-assembly.

Microfibrils are essential elements in elastic and nonelastic tissues contributing to homeostasis and growth factor regulation. Fibrillins form the core of these multicomponent assemblies. Various human genetic disorders, the fibrillinopathies, arise from mutations in fibrillins and are frequently associated with aberrant microfibril assembly.

Proteolytic enzymes in skeletal development: histochemical methods adapted to the study of matrix lysis during the transformation of a "cartilage model" into bone.

The replacement of a "cartilage model" by definitive bone is characterized by a series of localized excavations of the cartilage which are eventually followed by bone deposition. Each excavation requires lysis of cartilage components (defined here as the breakdown of a peptide bond) and their eventual resorption (defined here as microscopical visible cartilage loss). More precisely we have proposed that the lysis is affected by proteases capable of breaking down the main proteoglycan "aggrecan" and the main fibril element, "type II collagen".

Protease analysis by neoepitope approach reveals the activation of MMP-9 is achieved proteolytically in a test tissue cartilage model involved in bone formation.

A principle of regulation of matrix metalloproteinase (MMP) activity has been introduced as the cysteine-switch mechanism of activation (Springman et al. 1990). According to this mechanism, a critical Cys residue found in the auto-inhibitory propeptide domain of latent proenzyme is important to determine whether or not activation is turned on or off.

Use of anti-neoepitope antibodies for the analysis of degradative events in cartilage and the molecular basis for neoepitope specificity.

Degradation of the cartilage proteoglycan, aggrecan, is an essential aspect of normal growth and development, and of joint pathology. The roles of different proteolytic enzymes in this process can be determined from the sites of cleavage in the aggrecan core protein, which generates novel termini (neoepitopes). Antibodies specific for the different neoepitopes generated by such cleavage events provide powerful tools with which to analyse these processes.