Elucidating the mechanisms involved in growth and remodeling of cartilage is of paramount importance for our understanding of skeletal development and of pathological conditions of the skeletal system. These processes can be advantageously studied in the epiphyseal growth zone, that region of developing long bones in which elongation is achieved. Here, a continuum of changes in cartilaginous matrices occurs as young growth cartilage matures and becomes hypertrophic, and ultimately is replaced by a marrow cavity and/or bon tissue. Each stage requires precisely-controlled changes in cellular and matrix components-the latter involving de novo synthesis of new components, modifications of preexisting ones, and ultimately the degradation and removal of all of them. Based on our previous studies, we will investigate three separate, but related, aspects of the cartilage in the growth region. These are: (1) the transcription al regulation of type X collagen the best characterized component of hypertrophic cartilage matrix, (2) the functional roles of three proteins (plasma transglutaminase, adseverin and galectin) we have identified as being upregulated in hypertropic chondrocytes, and (3) the regulatory roles of the perichondrium. The transcriptional studies on the type X collagen gene will involve the positive regulation effected by the Sp 1 family of transcription factors in hypertrophic chondrocytes, and the mechanism for rendering these inactive in nonhypertrophic cells. In addition they will address the possibility that the transcriptional machinery utilized by the type X gene responds to elevated Ca++, and may even differ from that utilized by most other genes. We will address further the possibility that hypertrophic chondrocytes regulate the crosslinking enzyme plasma transglutaminase to facilitate cell death, and matrix remodeling and removal. We will examine whether the cytoskeletal- modifying enzyme adseverin is involved in regulated secretion by hypertrophic cells, and whether this process, or others of the hypertrophic program, are facilitated by elevated intracellular Ca++ produced by galectin 3. WE will examine further the perichondrially-mediated influences on cartilage growth, and on chondrocyte proliferation, differentiation, and enlargement, and lastly we will isolate and identify the factors involved.
Showing the most recent 10 out of 90 publications
