Skeletal system

We are investigating how FGF signaling regulates osteoblast function and bone density during development and aging. We have shown that FGF signaling in the osteoprogenitor cell indirectly regulates growth plate chondrocyte proliferation and differentiation and directly regulates the metabolic activity of osteoblasts. We have also identified an autocrine FGF signal that regulates articular chondrocyte differentiation. Through these mechanisms, FGF signaling regulates longitudinal bone growth, bone mass, and homeostasis of articular cartilage.

Recent Publications

1.    Colvin JS, Bohne BA, Harding GW, McEwen DG & Ornitz DM (1996) Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat. Genet. 12(4):390-397.
2.    Naski MC, Colvin JS, Coffin JD & Ornitz DM (1998) Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. Development 125(24):4977-4988.
3.    Henderson JE, Naski MC, Aarts MM, Wang D, Cheng L, Goltzman D & Ornitz DM (2000) Expression of FGFR3 with the G380R achondroplasia mutation inhibits proliferation and maturation of CFK2 chondrocytic cells. J. Bone Miner. Res. 15(1):155-165.
4.    Liu Z, Xu J, Colvin JS & Ornitz DM (2002) Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. Genes Dev. 16(7):859-869.  PMCID: PMC186326.
5.    Ornitz DM & Marie PJ (2002) FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev. 16(12):1446-1465.
6.    Yu K, Xu J, Liu Z, Sosic D, Shao J, Olson EN, . . . Ornitz DM (2003) Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth. Development 130(13):3063-3074.  PMCID: PMID: 12756187.
7.    Xiao L, Naganawa T, Obugunde E, Gronowicz G, Ornitz DM, Coffin JD & Hurley MM (2004) Stat1 controls postnatal bone formation by regulating fibroblast growth factor signaling in osteoblasts. J. Biol. Chem. 279(26):27743-27752.
8.    Ornitz DM (2005) FGF signaling in the developing endochondral skeleton. Cytokine Growth Factor Rev. 16(2):205-213.
9.    Jacob AL, Smith C, Partanen J & Ornitz DM (2006) Fibroblast growth factor receptor 1 signaling in the osteo-chondrogenic cell lineage regulates sequential steps of osteoblast maturation. Dev Biol 296(2):315-328.  PMCID: 2077084.
10.    Perlyn CA, Morriss-Kay G, Darvann T, Tenenbaum M & Ornitz DM (2006) A model for the pharmacological treatment of crouzon syndrome. Neurosurgery 59(1):210-215; discussion 210-215.  PMCID: PMC2267918.
11.    Hung IH, Yu K, Lavine KJ & Ornitz DM (2007) FGF9 regulates early hypertrophic chondrocyte differentiation and skeletal vascularization in the developing stylopod. Dev Biol 307(2):300-313.  PMCID: PMC2267922.
12.    Liu Z, Lavine KJ, Hung IH & Ornitz DM (2007) FGF18 is required for early chondrocyte proliferation, hypertrophy and vascular invasion of the growth plate. Dev Biol 302(1):80-91.
13.    Yu K & Ornitz DM (2008) FGF signaling regulates mesenchymal differentiation and skeletal patterning along the limb bud proximodistal axis. Development 135(3):483-491.
14.    Schmid GJ, Kobayashi C, Sandell LJ & Ornitz DM (2009) Fibroblast growth factor expression during skeletal fracture healing in mice. Dev Dyn 238(3):766-774.  PMCID: 2688661.
15.    Martinez MD, Schmid GJ, McKenzie JA, Ornitz DM & Silva MJ (2010) Healing of non-displaced fractures produced by fatigue loading of the mouse ulna. Bone 46(6):1604-1612.  PMCID: PMCID: PMC2875275.
16.    Long F & Ornitz DM (2013) Development of the endochondral skeleton. Cold Spring Harb Perspect Biol 5(1):a008334.  PMCID: PMC3579395.
17.    Chen J, Shi Y, Regan J, Karuppaiah K, Ornitz DM & Long F (2014) Osx-Cre Targets Multiple Cell Types besides Osteoblast Lineage in Postnatal Mice. PLoS One 9(1):e85161.  PMCID: PMC3893188.
18.    Ornitz DM & Marie PJ (2015) Fibroblast growth factor signaling in skeletal development and disease. Genes Dev. 29(14):1463-1486.  PMCID: PMC4526732.
19.    Yu K, Karuppaiah K & Ornitz DM (2015) Mesenchymal fibroblast growth factor receptor signaling regulates palatal shelf elevation during secondary palate formation. Dev Dyn 244(11):1427-1438.  PMCID: PMC4619180.
20.    Hung IH, Schoenwolf GC, Lewandoski M & Ornitz DM (2016) A combined series of Fgf9 and Fgf18 mutant alleles identifies unique and redundant roles in skeletal development. Dev Biol 411(1):72-84.  PMCID: PMC4801039.
21.    Karuppaiah K, Yu K, Lim J, Chen J, Smith C, Long F & Ornitz DM (2016) FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth. Development 143(10):1811-1822.  PMCID: PMC4874483.
22.    Luo X, Fu Y, Loza AJ, Murali B, Leahy KM, Ruhland MK, . . . Stewart SA (2016) Stromal-Initiated Changes in the Bone Promote Metastatic Niche Development. Cell Rep 14(1):82-92.  PMCID: PMC4706805.

23. Ornitz DM & Legeai-Mallet L (2016) Achondroplasia: Development, Pathogenesis, and Therapy. Dev Dyn in press.