All ETDs from UAB

Advisory Committee Chair

Amjad Javed

Advisory Committee Members

Skip Gilbert

Dobrawa Napierala

Rosa Serra

Jianbo Wang

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


The Runx2 transcription factor is necessary for commitment and differentiation of mesenchymal cells into the chondroblasts, osteoblasts and odontoblasts. Runx2 induces the expression of several key genes involved in mineralization of both the bone and dentin matrices. Global Runx2-null mice are completely void of mineralized tissue and do not express osteoblast markers, indicating that Runx2 is required for commitment to the osteoblast lineage. Tooth development in Runx2-null mice is arrested in the bell stage, prior to the differentiation of odontoblasts. Thus, Runx2 is essential for development of osteoblast and odontoblast lineages. However, the functional requirements of Runx2 after commitment to the osteoblast and odontoblast lineages remain unknown. Here, we deleted Runx2 specifically in osteoblasts and odontoblasts to study osteogenesis and odontogenesis during embryonic and postnatal life. Surprisingly, Runx2 mutant mice were born alive and were similar in size to wild-type litter mates. However, skeletal analysis revealed delayed formation and decreased calcification of intramembranous bones in Runx2 mutant mice. Though calcification of endochondral bones was reduced, bone length and width were not affected in newborn homozygous mice. Runx2 mutants showed progressive retardation in postnatal growth. By one month of age, Runx2 mutant mice exhibited impaired appositional growth of the long bones. Notably, the length of bones was similar between wild-type and homozygous mice. Consistent with this observation, chondrocyte differentiation and cartilage growth in mutants was similar to wild-type mice from birth to 3 months of age. Analysis of the femur and tibia of homozygous mice revealed a significant decrease in bone mass and mineral density. Decreased bone formation was associated with decreased gene expression of osteoblast markers and impaired collagen assembly in the extracellular matrix. Consequently, Runx2 mutant bones exhibited decreased stiffness and structural integrity. By 3 months of age, bone acquisition in mutant mice was roughly half of wild type littermates. Histomorphometric analyses showed that despite a marked decrease in bone formation rate and acquisition, the number of osteoblasts was similar between wild type and homozygous mice. In addition to impaired osteoblast function, mutant mice showed markedly decreased osteoclast number and postnatal bone resorption. Thus, the low bone mass phenotype was not associated with an increase in bone resorption, as both the number and activity of osteoclasts were decreased in mutant mice at all stages analyzed. The dental phenotype was also analyzed in Runx2 mutant mice at newborn and post-eruptive stages. Surprisingly, molars of homozygous mice reached the bell stage of tooth development by birth. In addition, both odontoblasts and ameloblasts were elongated and polarized in Runx2 mutants. At 1 month of age, the volume of dentin matrix in homozygous tooth organs was comparable to wild-type mice. Moreover, odontogenesis progressed normally during postnatal tooth development, and odontoblast processes that extended throughout the dentin layer was seen in both litter mates. Similarly, root formation was not disrupted, as histological analysis of Runx2 mutant molars revealed a layer of cementum attached to the surrounding alveolar bone by PDL fibers. Together, these data demonstrate that Runx2 activity is required in osteoblasts for embryonic and postnatal bone synthesis and remodeling. However, Runx2 function is not essential for the development of tooth organs after commitment to the odontoblast lineage.



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