We generated preliminary evidence showing that the number of osteoclasts in the fracture calluses of mice haploinsufficient for Runx1 is increased compared to wild type littermates. Furthermore, we found that targeted deletion of Runx1 in osteoclast precursors led to 25-30% decrease in trabecular bone mass and a 40-50% increase in bone resorption. Finally, we determined that Runx1 inhibits the expression of osteoclast specific genes in vitro. Thus, we hypothesized that Runx1 inhibits myeloid precursor cell differentiation into mature osteoclasts and in this way alters skeletal homeostasis and repair. We propose to: 1. Evaluate the role of Runx1 in regulating osteoclasts during bone remodeling and fracture repair.
(Aim 1). We propose to determine whether: (i) Runx1 is a transcriptional repressor of osteoclast differentiation and function in vivo and (ii) if conditional deletion of Rux1 in precursors but not mature osteoclasts will impair fracture healing. 2. Define the mechanisms underlying Runx1-mediated inhibition of osteoclastogenesis.
(Aim 2). We propose to determine whether (i) Runx1 is critical for early but not late osteoclast differentiation;(ii) examine if Rux1-mediated inhibition of osteoclastogenesis depends on inhibition of RANK-signaling;(iii) Runx1 alters osteoclast precursor lineage commitment and differentiation by regulating critical genes;(iv) Runx1 regulates myeloid precursor commitment towards various lineage fates. Our proposed experiments will provide a novel and integrated mechanistic insight into the transcriptional repression of osteoclast differentiation during skeletal regeneration and repair.
Skeletal repair involves remodeling of the bone at the fracture site. We propose to examine a novel role for a protein named Runx1 in bone resorption during fracture healing. Information obtained from this project may help develop new agents that accelerate bone repair or can be used to treat diseases like osteoporosis.
|Lorenzo, Joseph (2017) The many ways of osteoclast activation. J Clin Invest 127:2530-2532|
|Paglia, David N; Yang, Xiaochuan; Kalinowski, Judith et al. (2016) Runx1 Regulates Myeloid Precursor Differentiation Into Osteoclasts Without Affecting Differentiation Into Antigen Presenting or Phagocytic Cells in Both Males and Females. Endocrinology 157:3058-69|
|Drissi, Hicham; Paglia, David N; Alaee, Farhang et al. (2014) Constructing the toolbox: Patient-specific genetic factors of altered fracture healing. Genes Dis 1:140-148|
|Soung, Do Y; Kalinowski, Judith; Baniwal, Sanjeev K et al. (2014) Runx1-mediated regulation of osteoclast differentiation and function. Mol Endocrinol 28:546-53|