Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Hormone or other secreted growth regulatory factor,...
Reexamination Certificate
1998-07-24
2002-10-15
Spector, Lorraine (Department: 1646)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Hormone or other secreted growth regulatory factor,...
C514S043000, C530S399000
Reexamination Certificate
active
06464983
ABSTRACT:
2. FIELD OF THE INVENTION
This invention relates generally to the field of growth factors and specifically to Connective Tissue Growth Factor (CTGF) and methods of use thereof.
3. BACKGROUND OF THE INVENTION
A. The Role Of Growth Factors in Bone and Cartilage Formation
Bone And Cartilage Formation. The formation of tissue and organs in all multicellular organisms that arise from a single fertilized egg requires the differentiation of specialized cell types from non-differentiated stem cells. As embryogenesis proceeds, more highly specialized cell types and complex structures are formed. Currently, however, little concrete information is available on the identification of the specific factors or the mechanism of action of these factors on skeletal or cartilage formation in vertebrate animals, including humans.
There are two common types of bone formation in the mammalian system: intramembranous ossification and ehdochondral ossification. The formation of the bones of the skull are an example of intramembranous ossification. There, mesenchymal cells from the neural crest interact with the extracellular matrix of the cranial epithelial cells and form bone. Hall,
Amer. Sci
. , 1988, 76174-181. Mesenchymal cells condense into small islands and differentiate into osteoblasts and capillaries. The osteoblasts secrete a specific type of extracellular matrix, (osteoid) which is capable of binding calcium salts.
Endochondral ossification is the process by which the long bones of the axial skeleton (arms and legs), and the vertebra and ribs form. Hall, supra. During this process the formation of bone occurs via a cartilaginous tissue intermediate stage. In mammals, the long bones form from certain mesenchymal cells in the embryonic limb buds. These cells form chondrocytes, and secrete a cartilaginous matrix. Other surrounding mesenchymal cells form the perichondrium (ultimately, the periosteum). In some cases, chondrocytes adjacent to the region where chondrocytes are proliferating and forming differentiate into hypertrophic chondrocytes.
Hypertrophic chondrocytes produce a different type of matrix, and alter their tissue orientation to form the physis. The structure of the physis is arranged in multiple 30 cellular columns composed of zones of cellular hypertrophy, proliferation, ossification and vascularization. Hall, supra; Gilbert, “Transcriptional regulation of gene expression,” DEVELOPMENTAL BIOLOGY, 5th ed. Sinaur Assoc., p. 387-390 (1994). This results in a gradation of cell transformation from chondrocytes to osteoblasts which form the mineralized-bone.
Endochondral ossification is an active, ongoing process that occurs in mammals during the growth from infant to adult. The differentiation of mesenchymal cells to chondrocytes, their proliferation and replacement by osteoblasts are dependent on growth factors (including the TGF-&bgr; family), and on the mineralization of the matrix. Tuan, 1984
, J. Exp. Zool
. (suppl.) 1:1-13 (1984); Syfestad and Caplan, 1984
, Devel. Biol
. 104:348-386.
With regard to connective tissue, it is felt that all skeletal elements in mammals are derived from a single stem cell that is capable of differentiating into the specific cell types that compose muscle, cartilage, bone and tendon. These cells also appear to be capable of differentiating into adipose tissue.
The Relevant Art Related To Growth Factors And The Formation Of Bone And Cartilage. Prior to the present invention, it was known generally that growth factors comprise a class of secreted polypeptides that stimulate target cells to proliferate, differentiate and organize developing tissues. Typically, a growth factor's activity is dependent on its ability to bind to specific receptors, thereby stimulating a signaling event within the cell. Examples of some well-studied growth factors include platelet-derived growth factor (PDGF), insulin-like growth factor (IGF-I), transforming growth factor beta family (TGF-&bgr;), transforming growth factor alpha (TGF-&agr;), epidermal growth factor (EGF), and fibroblast growth factors (FGF).
Effect Of TGF-&bgr; On Chondrocyte Growth, Differentiation and Cartilage Formation. The TGF-&bgr;s play a role in chondrogenesis. As previously reported, TGF-&bgr;1 and TGF-&bgr;2 increase chondrogenesis in embryonic rat mesenchymal cells (Seyedin,et al.., 1987
, J. Biol. Chem
. 262: 1946-1947), and either isoform can induce formation of chondroblasts from murine muscle mesenchymal cells in culture. Seyedin. et al., 1986
, J. Biol. Chem
. 261: 5693-5695. Application of the TGF-&bgr;s to murine embryonic prechondroid tissues increases differentiation of mesenchymal cells, production of proteoglycans, and replication of chondroblasts. Centrella, et al., 1994
, Endocrine Reviews
15:27-38; Thorp and Jakowlew, 1994
, Bone
15: 59-64.
Using in-situ hybridization, decreased levels of TGF-&bgr;3 were found in the growth plates of animals with three separate disorders where chondrocytes cease to differentiate. Id. In organ cultures of bovine articular cartilage, type II collagen and proteoglycan synthesis were increased after TGF-&bgr; administration. Morales and Roberts, 1988
, J. Biol. Chem
. 263: 12828-12831. In contrast, the TGF-&bgr;s have been shown to decrease expression of type II and type X cartilage-specific collagens, synthesis of chondrocyte proteoglycans, and activity of alkaline phosphatase in cultured chondroid cells. Mundy. “The effects of TGF-&bgr; on bone,”
Clinical Applications of TGF-&bgr;.,
1991, Wiley Chichester, Ciba Foundation Symposium 157: 137-151. Rabbit growth plate chondrocyte differentiation is inhibited by TGF-&bgr;, while growth plate chondrocyte mitogenesis is increased. Kato, et al., 1988
, Proc. Natl. Acad. Sci. USA
85: 9552-9556. In addition, large concentrations of TGF-&bgr;1 or TGF-&bgr;2 added to an osteoinductive model favor cartilage, rather than the preference for bone formation, when smaller doses are used. Mundy, supra. This accumulation of apparently contradictory data has hindered efforts to define a function for the TGF-&bgr;s in chondrogenesis.
The Bone Morphogenic Proteins And Bone Formation. A family of proteins termed the bone morphogenetic proteins (BMP's are capable of inducing ectopic bone formation in certain mammalian species. With the exception of BMP-1, which encodes a metalloprotease, all of these proteins have structures that are related to TGF-&bgr;. However, it is not known which, if any of the BMP's are responsible for the regulation of bone formation during normal embryogenesis.
BMP's were first isolated from demineralized bone as factors that induced bone at extra skeletal ectopic sites. Three peptides were originally identified as BMP-1, BMP-2A, and BMP-3. Celeste, et al., 1990
, Proc. Natl Acad. Sci. USA
87: 984.3-9847; Kubler and Urist, 1990
, Clin. Orthopedics and Rel. Res
. 258: 279-294. The latter two BMPs are members of the TGF-&bgr; superfamily. Subsequently, five more closely related members of the BMP group have been identified and cloned. BMP-5, BMP-6, and BMP-7 are most similar to vgr/60A, while BMP-2 and BMP-4 are more similar to Decapentaplegic. Both vga/60A and Decapentaplegic are Drosophila genes that control dorsal/ventral axis pattern formation. Hoffman, 1992
, Mol. Repro and Dev
. 32: 173-178.
In-situ hybridization has localized BMP's gene transcription to areas of bone formation in the limb bud at specific times during development, suggesting a physiologic role. The BMPs induce adventitial post-fetal mesenchymal cells to switch from fibrogenetic to chondroosteoprogenetic patterning. Kubler and Urist, supra. Several lines of data suggest the BMPs may act synergistically with TGF-&bgr;s to initiate the cascade of osteoinduction in-vivo. In murine subcutis, TGF-&bgr;1 enhances the production of ectopic bone by most BMPs. BMP-6 (also known as VGR-1) is expressed in hypertrophic cartilage at the same time and in the same areas as the TGF-&bgr;s, and is associated with collagen type X expression. See, Celeste, et al., supra.
The addition of TGF&bgr;-2 to bone explants w
Gray Cary Ware & Freidenrich LLP
Haile Lisa A.
Imbra Richard J.
Spector Lorraine
University of South Florida
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