The skeletal site-specific role of connective tissue growth factor in prenatal osteogenesis.
BACKGROUND
Connective tissue growth factor (CTGF/CCN2) is a matricellular protein that is highly expressed during bone development. Mice with global CTGF ablation (knockout, KO) have multiple skeletal dysmorphisms and perinatal lethality. A quantitative analysis of the bone phenotype has not been conducted.


RESULTS
We demonstrated skeletal site-specific changes in growth plate organization, bone microarchitecture, and shape and gene expression levels in CTGF KO compared with wild-type 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 nonallometric shape changes. Localized differences in skull morphology included increased skull width and decreased skull length. Dysregulation of the transforming growth factor-β-CTGF axis coupled with unique morphologic traits provides a potential mechanistic explanation for the skull phenotype.


CONCLUSIONS
We present novel data on a skeletal phenotype in CTGF KO mice, in which ablation of CTGF causes site-specific aberrations in bone formation.
Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Alex G
AG
Lambi
Talia L
TL
Pankratz
Christina
C
Mundy
Maureen
M
Gannon
Mary F
MF
Barbe
Joan T
JT
Richtsmeier
Steven N
SN
Popoff
D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D049109:Cell Proliferation; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D006132:Growth Plate / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity / Q000502:physiology; D010012:Osteogenesis / Q000502:physiology*; D012886:Skull / Q000196:embryology*; D013131:Spine / Q000196:embryology*
D000943:Antigens, Differentiation; C526318:CCN2 protein, mouse; D055513:Connective Tissue Growth Factor