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Temple University

1. Lambi, Alex G. The Intricate Role of Connective Tissue Growth Factor (CTGF/CCN2) in Prenatal Osteogenesis: A Heretofore Oversimplified Dogma of the CCN Field.

Degree: PhD, 2015, Temple University

Cell Biology

Connective tissue growth factor (CTGF/CCN2) is axiomatically necessary for proper skeletal development and function. We need not look further than the studies that have been done to date utilizing mice genetically engineered to lack CTGF production. These CTGF null or knockout (KO) mice fail to form a normal murine skeleton and instead yield one littered with bony dysmorphisms, including incompetent craniofacial development, kinked limb bones, and misshapen ribs that are not conducive to proper respiratory function. As a result, the global lack of CTGF is incompatible with postnatal life. A closer look at several sites demonstrated defects in physiologic processes necessary for bone formation - angiogenesis, chondrogenesis, and osteogenesis. Therefore, the dogma in the CCN protein field to date has been that systemic ablation of CTGF production in vivo results in global defects in bone development. We believe this dogma is an oversimplification of the role of CTGF on skeletal development. Our initial impetus leading us to this belief was the gross identification of the specific skeletal sites malformed in CTGF KO mice, in particular the bones of the limbs. While in the lower limb of CTGF KO mice the tibiae and fibulae are misshapen, the adjacent femora and digits are phenotypically normal. The same is true for the upper limb, in which the radii and ulnae are phenotypically abnormal while the humeri and digits are normal. Therefore, we believe that the role of CTGF in skeletogenesis is site-specific such that its loss affects local skeletal patterning and/or mechanobiological cues resulting in the unique phenotype seen in CTGF KO mice. The research of this dissertation constitutes a comprehensive skeletal analysis of CTGF KO mice and in so doing we determined the extent and location of skeletal abnormalities. We found skeletal site-specific changes in growth plate organization, bone microarchitecture and shape and gene expression levels in CTGF KO compared to wild-type (WT) mice. Growth plate malformations included reduced proliferation zone and increased hypertrophic zone lengths. Appendicular skeletal sites demonstrated decreased metaphyseal trabecular bone, while having increased mid-diaphyseal bone and osteogenic expression markers. Axial skeletal analysis showed decreased bone in caudal vertebral bodies, mandibles, and parietal bones in CTGF KO mice, with decreased expression of osteogenic markers. Analysis of skull phenotypes demonstrated global and regional differences in CTGF KO skull shape resulting from allometric (size-based) and non-allometric shape changes. Localized differences in skull morphology included increased skull width and decreased skull length. We further continued the skeletal characterization of CTGF KO bones with an analysis of bone cell ultrastructure and matrix composition. These studies demonstrated that, while CTGF is not necessary for complete morphologic maturation of bone cells, global ablation results in ultrastructural features not commonly seen in WT bones. Our…

Advisors/Committee Members: Popoff, Steven N.;, Barbe, Mary F., Rizzo, Victor, Soprano, Dianne R., Richtsmeier, Joan T.;.

Subjects/Keywords: Cellular biology; Developmental biology;

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Lambi, A. G. (2015). The Intricate Role of Connective Tissue Growth Factor (CTGF/CCN2) in Prenatal Osteogenesis: A Heretofore Oversimplified Dogma of the CCN Field. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,233693

Chicago Manual of Style (16th Edition):

Lambi, Alex G. “The Intricate Role of Connective Tissue Growth Factor (CTGF/CCN2) in Prenatal Osteogenesis: A Heretofore Oversimplified Dogma of the CCN Field.” 2015. Doctoral Dissertation, Temple University. Accessed September 22, 2020. http://digital.library.temple.edu/u?/p245801coll10,233693.

MLA Handbook (7th Edition):

Lambi, Alex G. “The Intricate Role of Connective Tissue Growth Factor (CTGF/CCN2) in Prenatal Osteogenesis: A Heretofore Oversimplified Dogma of the CCN Field.” 2015. Web. 22 Sep 2020.

Vancouver:

Lambi AG. The Intricate Role of Connective Tissue Growth Factor (CTGF/CCN2) in Prenatal Osteogenesis: A Heretofore Oversimplified Dogma of the CCN Field. [Internet] [Doctoral dissertation]. Temple University; 2015. [cited 2020 Sep 22]. Available from: http://digital.library.temple.edu/u?/p245801coll10,233693.

Council of Science Editors:

Lambi AG. The Intricate Role of Connective Tissue Growth Factor (CTGF/CCN2) in Prenatal Osteogenesis: A Heretofore Oversimplified Dogma of the CCN Field. [Doctoral Dissertation]. Temple University; 2015. Available from: http://digital.library.temple.edu/u?/p245801coll10,233693

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