This project explores the molecular and physiological interactions between two crucial regulators of craniofacial development, bone repair/regeneration, and optimal bone mass accrual and maintenance: Runx2 and Axin2. Runx2 (Cbfa1) is a transcription factor required for osteoblastogenesis and chondrocytes hypertrophy. Runx2-deficiency is postnatally lethal, whereas Runx2-haploinsufficiency causes cleidocranial dysplasia (CCD) and osteopenia. The only known biologic means to at least partially rescue the CCD phenotype in Runx2 mice is by inhibiting Gsk32. Axin2 is the concentration- limiting scaffolding protein that assembles Gsk32, 2-catenin and other components into the 2-catenin destruction complex. Axin2 is a negative feedback regulator of canonical Wnt signaling and slows osteoblast proliferation. Interestingly, Axin2 knockout mice have craniosynostosis (CS) and high trabecular bone mass density. In humans, AXIN2 mutations are linked to familial tooth agenesis. Thus, Axin2-deficiency and Runx2- haploinsufficiency cause opposing craniofacial and trabecular bone phenotypes. We show that Axin2 levels are increased in Runx2-deficient cells. The central hypothesis of this project is that Runx2 actively represses Axin2 to enhance Wnt/ 2-catenin signaling in bone cells.
We aim to determine if canonical Wnt signaling is altered in osteoblast progenitors from Runx2-/- mice, define the molecular mechanisms whereby Runx2 regulates Axin2 transcription, and to quantitatively assess the skeletal phenotypes of "double mutant" Runx2: Axin2-/- mice relative to wild type, Runx2 and Axin2-/- mice.
Bone disorders or damage can afflict humans of any age. One in 750 live births is associated with a craniofacial abnormality and approximately 1 in 2000 children develops a form of craniosynostosis. During their lifetimes, half of all women and a quarter of men can expect to suffer an osteoporosis-related fracture. This project explores the molecular interactions between two crucial regulators of suture closure, bone repair/regeneration, and optimal bone mass accrual and maintenance: Runx2 and Axin2. The proposed project is significant because Runx2 is required for osteoblastogenesis and Axin2 is a crucial negative regulator of the Wnt-2-catenin signaling pathway, which is a target for new anabolic agents. Because Axin2 is an intracellular inhibitor of 2-catenin and Lrp5 signaling, its activity could theoretically decrease the efficiency of emerging anabolic therapies that neutralize extracellular Wnt/Lrp5/6 inhibitors (e.g. anti-Sclerostin or anti-Dkk1 antibodies). The work will have collective impact because Runx2 and Axin2 also contribute to chondrocyte maturation and are tumor suppressors.
|Ryan, Zachary C; Craig, Theodore A; McGee-Lawrence, Meghan et al. (2015) Alterations in vitamin D metabolite, parathyroid hormone and fibroblast growth factor-23 concentrations in sclerostin-deficient mice permit the maintenance of a high bone mass. J Steroid Biochem Mol Biol 148:225-31|
|Ryan, Zachary C; Craig, Theodore A; Salisbury, Jeffrey L et al. (2014) Enhanced prostacyclin formation and Wnt signaling in sclerostin deficient osteocytes and bone. Biochem Biophys Res Commun 448:83-8|
|McGee-Lawrence, Meghan E; Carpio, Lomeli R; Bradley, Elizabeth W et al. (2014) Runx2 is required for early stages of endochondral bone formation but delays final stages of bone repair in Axin2-deficient mice. Bone 66:277-86|
|Dudakovic, Amel; Camilleri, Emily; Riester, Scott M et al. (2014) High-resolution molecular validation of self-renewal and spontaneous differentiation in clinical-grade adipose-tissue derived human mesenchymal stem cells. J Cell Biochem 115:1816-28|
|McGee-Lawrence, Meghan E; Bradley, Elizabeth W; Dudakovic, Amel et al. (2013) Histone deacetylase 3 is required for maintenance of bone mass during aging. Bone 52:296-307|
|Dudakovic, Amel; Evans, Jared M; Li, Ying et al. (2013) Histone deacetylase inhibition promotes osteoblast maturation by altering the histone H4 epigenome and reduces Akt phosphorylation. J Biol Chem 288:28783-91|
|McGee-Lawrence, Meghan E; Ryan, Zachary C; Carpio, Lomeli R et al. (2013) Sclerostin deficient mice rapidly heal bone defects by activating *-catenin and increasing intramembranous ossification. Biochem Biophys Res Commun 441:886-90|
|McGee-Lawrence, Meghan E; Li, Xiaodong; Bledsoe, Krista L et al. (2013) Runx2 protein represses Axin2 expression in osteoblasts and is required for craniosynostosis in Axin2-deficient mice. J Biol Chem 288:5291-302|
|Monroe, David G; McGee-Lawrence, Meghan E; Oursler, Merry Jo et al. (2012) Update on Wnt signaling in bone cell biology and bone disease. Gene 492:1-18|
|Bradley, Elizabeth W; McGee-Lawrence, Meghan E; Westendorf, Jennifer J (2011) Hdac-mediated control of endochondral and intramembranous ossification. Crit Rev Eukaryot Gene Expr 21:101-13|