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.
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.
|Bradley, Elizabeth W; Carpio, Lomeli R; Olson, Eric N et al. (2015) Histone deacetylase 7 (Hdac7) suppresses chondrocyte proliferation and Î²-catenin activity during endochondral ossification. J Biol Chem 290:118-26|
|Bradley, Elizabeth W; Carpio, Lomeli R; Newton, Alexandra C et al. (2015) Deletion of the PH-domain and Leucine-rich Repeat Protein Phosphatase 1 (Phlpp1) Increases Fibroblast Growth Factor (Fgf) 18 Expression and Promotes Chondrocyte Proliferation. J Biol Chem 290:16272-80|
|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|