Studies of mouse and human genetics show that canonical Wnt signaling is required for normal bone development as well as acquisition of normal bone mass. Canonical Wnt signaling is strongly anabolic for bone. Consequently, understanding how canonical Wnt signaling induces bone will illuminate pathways that can be manipulated to increase bone mass for the treatment of osteoporosis. Because canonical Wnt signaling increases the protein levels of beta-catenin (bcat), which then moves to the nucleus and induces gene expression, we hypothesized that bcat cooperates with bone-specific transcription pathways to induce genes responsible for Wnt- induced bone formation. Significantly, in preliminary data we show that fibroblast growth factor 18 (FGF18) expression requires and is directly induced by canonical Wnt signaling. Moreover, the osteoblast-specific transcription factor, Runx2, binds to the Wnt-dependent transcription factor LEF/TCF and thereby stimulates the FGF18 promoter. Thus, FGF18 expression is directly linked to bone-specific and Wnt-dependent transcription. Given these direct links to the essential pathways of bone, we hypothesize that induction of FGF18 is required for the anabolic effects of Wnt signaling in bone. We further hypothesize that the Runx2-LEF/TCF transcription complex regulates a set of genes that induce a specific early stage of osteoblast differentiation. To test our hypotheses and advance new therapies for bone disease we will pursue the following specific aims: 1) determine the protein domains and thermodynamic parameters that govern assembly of the Runx2-LEF complex and its affinity for DNA, 2) identify osteoblast-relevant genes that are turned on (or off) by the convergence of Wnt signaling and Runx2, and 3) using mice with conditional loss and gain of function alleles for bcat define the requirement for FGFs and FGF signaling during canonical Wnt-induced osteoblast differentiation. These studies will provide an unprecedented view of the molecular events regulating osteoblast gene expression in respose to Wnt and FGF. Additionally, these studies will unravel how Wnt signaling induces formation of bone and in cooperation with other transcription factors regulates specific steps in the sequence of osteoblast differentiation. We anticipate that the completion of these studies will suggest new way to treating bone diseases like osteoporosis.
. This application aims to improve human health by advancing our understanding of the bone and bone producing cells. The completion of these studies will reveal new therapeutic targets and ways for treating bone disease like osteoporosis.
|Kämpjärvi, Kati; Park, Min Ju; Mehine, Miika et al. (2014) Mutations in Exon 1 highlight the role of MED12 in uterine leiomyomas. Hum Mutat 35:1136-41|
|Turunen, Mikko; Spaeth, Jason M; Keskitalo, Salla et al. (2014) Uterine leiomyoma-linked MED12 mutations disrupt mediator-associated CDK activity. Cell Rep 7:654-60|
|Liu, Z; Li, T; Reinhold, M I et al. (2014) MEK1-RSK2 contributes to Hedgehog signaling by stabilizing GLI2 transcription factor and inhibiting ubiquitination. Oncogene 33:65-73|
|Gu, Shoujun; Boyer, Thomas G; Naski, Michael C (2012) Basic helix-loop-helix transcription factor Twist1 inhibits transactivator function of master chondrogenic regulator Sox9. J Biol Chem 287:21082-92|
|Guntur, Anyonya R; Rosen, Clifford J; Naski, Michael C (2012) N-cadherin adherens junctions mediate osteogenesis through PI3K signaling. Bone 50:54-62|
|Guntur, Anyonya R; Reinhold, Martina I; Cuellar Jr, Joe et al. (2011) Conditional ablation of Pten in osteoprogenitors stimulates FGF signaling. Development 138:1433-44|
|Spaeth, Jason M; Kim, Nam Hee; Boyer, Thomas G (2011) Mediator and human disease. Semin Cell Dev Biol 22:776-87|