This project explores the molecular and physiological interactions between two crucial regulators of bone repair/regeneration and optimal bone mass accrual and maintenance: Runx2 and Axin2. Runx2 (Cbfa1) is a transcription factor required for osteoblastogenesis and chondrocyte 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 phenotype in Runx2 mice is by inhibiting Gsk3- 2. Axin2 is a concentration-limiting scaffolding protein that assembles Gsk3-2, 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 high trabecular bone mass. Thus, Axin2-deficiency and Runx2-haploinsufficiency cause opposing trabecular bone phenotypes. We show that Axin2 levels are increased in Runx2-deficient cells. The central hypothesis of this project is that Runx2 promotes bone mass and strength by actively repressing Axin2 and enhancing Wnt/2-catenin signaling in bone cells. The objective of this proposal is to quantitatively assess the phenotypes of "double mutant" Runx2:Axin2-/- mice relative to "single mutant" Runx2 or Axin2-/- mice and to determine if the interaction between Runx2 and Axin2 regulates bone cell differentiation.

Public Health Relevance

This project explores the molecular interactions between two crucial regulators of 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). An increased understanding of the interactions between Runx2 and Axin2 will have a 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 Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AR061873-02
Application #
8334718
Study Section
Special Emphasis Panel (ZRG1-F10B-S (20))
Program Officer
Chen, Faye H
Project Start
2011-08-04
Project End
2013-08-03
Budget Start
2012-08-04
Budget End
2013-08-03
Support Year
2
Fiscal Year
2012
Total Cost
$55,670
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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
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
Bradley, Elizabeth W; Carpio, Lomeli R; Westendorf, Jennifer J (2013) Histone deacetylase 3 suppression increases PH domain and leucine-rich repeat phosphatase (Phlpp)1 expression in chondrocytes to suppress Akt signaling and matrix secretion. J Biol Chem 288:9572-82