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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
3R01DE020194-04S1
Application #
8721570
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (02))
Program Officer
Wan, Jason
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$96,192
Indirect Cost
$35,694
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Bonin, Carolina A; Lewallen, Eric A; Baheti, Saurabh et al. (2016) Identification of differentially methylated regions in new genes associated with knee osteoarthritis. Gene 576:312-8
Dudakovic, Amel; Camilleri, Emily T; Riester, Scott M et al. (2016) Enhancer of Zeste Homolog 2 Inhibition Stimulates Bone Formation and Mitigates Bone Loss Caused by Ovariectomy in Skeletally Mature Mice. J Biol Chem 291:24594-24606
Weivoda, Megan M; Ruan, Ming; Hachfeld, Christine M et al. (2016) Wnt Signaling Inhibits Osteoclast Differentiation by Activating Canonical and Noncanonical cAMP/PKA Pathways. J Bone Miner Res 31:65-75
Dudakovic, Amel; Camilleri, Emily T; Lewallen, Eric A et al. (2015) Histone deacetylase inhibition destabilizes the multi-potent state of uncommitted adipose-derived mesenchymal stromal cells. J Cell Physiol 230:52-62
Gordon, Jonathan A R; Stein, Janet L; Westendorf, Jennifer J et al. (2015) Chromatin modifiers and histone modifications in bone formation, regeneration, and therapeutic intervention for bone-related disease. Bone 81:739-45
Lewallen, Eric Alexander; Riester, Scott M; Bonin, Carolina A et al. (2015) Biological strategies for improved osseointegration and osteoinduction of porous metal orthopedic implants. Tissue Eng Part B Rev 21:218-30
Bradley, Elizabeth W; Carpio, Lomeli R; van Wijnen, Andre J et al. (2015) Histone Deacetylases in Bone Development and Skeletal Disorders. Physiol Rev 95:1359-81
Dudakovic, Amel; Camilleri, Emily T; Xu, Fuhua et al. (2015) Epigenetic Control of Skeletal Development by the Histone Methyltransferase Ezh2. J Biol Chem 290:27604-17
McGee-Lawrence, Meghan E; Razidlo, David F (2015) Induction of fully stabilized cortical bone defects to study intramembranous bone regeneration. Methods Mol Biol 1226:183-92
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

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