Bone Biology

Current studies are investigating how FGF signaling regulates osteoblast and osteocyte function during development, homeostasis, and aging.
     Osteocytes function as master regulators of bone remodeling. Osteocyte death, one of the hallmarks of skeletal aging, is thought to contribute to the decline in bone strength with age and the increase in age-related fractures. In addition to aging, other factors, including unloading, sex hormone deficiency, glucocorticoid excess, inflammation, and osteoarthritis also lead to osteocyte death.
     We have discovered a novel role for Fibroblast Growth Factor Receptor (FGFR) signaling in the regulation of osteocyte survival and skeletal homeostasis (McKenzie, JBMR, 2019). We showed that conditional knockout (CKO) of FGFRs in mature osteoblasts and osteocytes in growing bone leads to osteocyte death in 3-week-old mice. We also temporally inactivated FGFRs in osteoblasts and osteocytes beginning at 3 weeks of age and found that this also resulted in osteocyte death. These observations and other ongoing studies suggest that in mature bone, FGFR signaling is required for osteocyte viability and consequently bone homeostasis.
     In previous studies (Karuppaiah, Development, 2016) we showed that FGF signaling also functions in an osteoprogenitor cell and through a feedback loop in the perichondrium, FGF signaling indirectly regulates growth plate chondrocyte proliferation and differentiation and directly regulates the metabolic activity of osteoblasts. Through these mechanisms, FGF signaling regulates longitudinal bone growth and bone mass.
     These studies are beginning to unravel the functions of FGFR during multiple stages in the osteoblast lineage.

Bone Biology publications:

  1. Marie PJ, Hurley M, Ornitz DM. Fibroblast growth factor (FGF) and FGF receptor families in bone. In: Bilezikian J, Martin TJ, Clemens T, Rosen C, editors. Principles of Bone Biology Academic Press; 2019. p. 2024.
  2. Ornitz DM, Marie PJ. Fibroblast growth factors in skeletal development. Curr Top Dev Biol. 2019;133:195-234 PubMed: PMID30902253.
  3. McKenzie J, Smith C, Karuppaiah K, Langberg J, Silva MJ, Ornitz DM. Osteocyte Death and Bone Overgrowth in Mice Lacking Fibroblast Growth Factor Receptors 1 and 2 in Mature Osteoblasts and Osteocytes. J Bone Miner Res. 2019;in press PubMed: PMID31206783.
  4. Yang LM, Ornitz DM. Sculpting the skull through neurosensory epithelial-mesenchymal signaling. Dev Dyn. 2018, 10.1002/dvdy.24664 PubMed: PMID30117627.
  5. Ornitz DM, Legeai-Mallet L. Achondroplasia: Development, pathogenesis, and therapy. Dev Dyn. 2017;246(4):291-309 PMCID: PMC5354942.
  6. Zhang H, Kamiya N, Tsuji T, Takeda H, Scott G, Rajderkar S, Ray MK, Mochida Y, Allen B, Lefebvre V, Hung IH, Ornitz DM, Kunieda T, Mishina Y. Elevated Fibroblast Growth Factor Signaling Is Critical for the Pathogenesis of the Dwarfism in Evc2/Limbin Mutant Mice. PLoS Genet. 2016;12(12):e1006510 PMCID: PMC5189957.
  7. Luo X, Fu Y, Loza AJ, Murali B, Leahy KM, Ruhland MK, Gang M, Su X, Zamani A, Shi Y, Lavine KJ, Ornitz DM, Weilbaecher KN, Long F, Novack DV, Faccio R, Longmore GD, Stewart SA. Stromal-Initiated Changes in the Bone Promote Metastatic Niche Development. Cell Rep. 2016;14(1):82-92 PMCID: PMC4706805.
  8. Karuppaiah K, Yu K, Lim J, Chen J, Smith C, Long F, Ornitz DM. FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth. Development. 2016;143(10):1811-22 PMCID: PMC4874483.
  9. Hung IH, Schoenwolf GC, Lewandoski M, Ornitz DM. A combined series of Fgf9 and Fgf18 mutant alleles identifies unique and redundant roles in skeletal development. Dev Biol. 2016;411(1):72-84 PMCID: PMC4801039.
  10. Yu K, Karuppaiah K, Ornitz DM. Mesenchymal fibroblast growth factor receptor signaling regulates palatal shelf elevation during secondary palate formation. Dev Dyn. 2015;244(11):1427-38 PMCID: PMC4619180.
  11. Ornitz DM, Marie PJ. Fibroblast growth factor signaling in skeletal development and disease. Genes Dev. 2015;29(14):1463-86 PMCID: PMC4526732.
  12. Chen J, Shi Y, Regan J, Karuppaiah K, Ornitz DM, Long F. Osx-Cre targets multiple cell types besides osteoblast lineage in postnatal mice. PLoS One. 2014;9(1):e85161 PMCID: PMC3893188.
  13. Long F, Ornitz DM. Development of the endochondral skeleton. Cold Spring Harb Perspect Biol. 2013;5(1):a008334 PMCID: PMC3579395.
  14. Martinez MD, Schmid GJ, McKenzie JA, Ornitz DM, Silva MJ. Healing of non-displaced fractures produced by fatigue loading of the mouse ulna. Bone. 2010;46(6):1604-12 PMCID: PMCID: PMC2875275.
  15. Schmid GJ, Kobayashi C, Sandell LJ, Ornitz DM. Fibroblast growth factor expression during skeletal fracture healing in mice. Dev Dyn. 2009;238(3):766-74 PMCID: 2688661.
  16. Yu K, Ornitz DM. FGF signaling regulates mesenchymal differentiation and skeletal patterning along the limb bud proximodistal axis. Development. 2008;135(3):483-91 PubMed: PMID18094024.
  17. Hung IH, Yu K, Lavine KJ, Ornitz DM. FGF9 regulates early hypertrophic chondrocyte differentiation and skeletal vascularization in the developing stylopod. Dev Biol. 2007;307(2):300-13 PMCID: PMC2267922.
  18. Perlyn CA, Morriss-Kay G, Darvann T, Tenenbaum M, Ornitz DM. A model for the pharmacological treatment of crouzon syndrome. Neurosurgery. 2006;59(1):210-5; discussion -5 PMCID: PMC2267918.
  19. Jacob AL, Smith C, Partanen J, Ornitz DM. Fibroblast growth factor receptor 1 signaling in the osteo-chondrogenic cell lineage regulates sequential steps of osteoblast maturation. Dev Biol. 2006;296(2):315-28 PMCID: 2077084.
  20. Yu X, Ibrahimi OA, Goetz R, Zhang F, Davis SI, Garringer HJ, Linhardt RJ, Ornitz DM, Mohammadi M, White KE. Analysis of the biochemical mechanisms for the endocrine actions of fibroblast growth factor-23. Endocrinology. 2005;146(11):4647-56 PubMed: PMID16081635.
  21. White KE, Cabral JM, Davis SI, Fishburn T, Evans WE, Ichikawa S, Fields J, Yu X, Shaw NJ, McLellan NJ, McKeown C, Fitzpatrick D, Yu K, Ornitz DM, Econs MJ. Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. Am J Hum Genet. 2005;76(2):361-7 PubMed: PMID15625620.
  22. Wang Y, Xiao R, Yang F, Karim BO, Iacovelli AJ, Cai J, Lerner CP, Richtsmeier JT, Leszl JM, Hill CA, Yu K, Ornitz DM, Elisseeff J, Huso DL, Jabs EW. Abnormalities in cartilage and bone development in the Apert syndrome FGFR2(+/S252W) mouse. Development. 2005;132(15):3537-48 PubMed: PMID15975938.
  23. Ornitz DM. FGF signaling in the developing endochondral skeleton. Cytokine Growth Factor Rev. 2005;16(2):205-13 PubMed: PMID15863035.
  24. Hu H, Hilton MJ, Tu X, Yu K, Ornitz DM, Long F. Sequential roles of Hedgehog and Wnt signaling in osteoblast development. Development. 2005;132(1):49-60 PubMed: PMID15576404.
  25. Xiao L, Naganawa T, Obugunde E, Gronowicz G, Ornitz DM, Coffin JD, Hurley MM. Stat1 controls postnatal bone formation by regulating fibroblast growth factor signaling in osteoblasts. J Biol Chem. 2004;279(26):27743-52 PubMed: PMID15073186.
  26. Valverde-Franco G, Liu H, Davidson D, Chai S, Valderrama-Carvajal H, Goltzman D, Ornitz DM, Henderson JE. Defective bone mineralization and osteopenia in young adult FGFR3-/- mice. Hum Mol Genet. 2004;13(3):271-84 PubMed: PMID14681299.
  27. Bialek P, Kern B, Yang X, Schrock M, Sosic D, Hong N, Wu H, Yu K, Ornitz DM, Olson EN, Justice MJ, Karsenty G. A twist code determines the onset of osteoblast differentiation. Dev Cell. 2004;6(3):423-35 PubMed: PMID15030764.
  28. Amizuka N, Davidson D, Liu H, Valverde-Franco G, Chai S, Maeda T, Ozawa H, Hammond V, Ornitz DM, Goltzman D, Henderson JE. Signalling by fibroblast growth factor receptor 3 and parathyroid hormone-related peptide coordinate cartilage and bone development. Bone. 2004;34(1):13-25 PubMed: PMID14751559.
  29. Yu K, Xu J, Liu Z, Sosic D, Shao J, Olson EN, Towler DA, Ornitz DM. Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth. Development. 2003;130(13):3063-74 PubMed: PMID12756187.
  30. Ornitz DM, Marie PJ. FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev. 2002;16(12):1446-65 PubMed: PMID12080084.
  31. Minina E, Kreschel C, Naski MC, Ornitz DM, Vortkamp A. Interaction of FGF, Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation. Dev Cell. 2002;3(3):439-49 PubMed: PMID12361605.
  32. Liu Z, Xu J, Colvin JS, Ornitz DM. Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. Genes Dev. 2002;16(7):859-69 PMCID: PMC186326.
  33. Wang Q, Green RP, Zhao G, Ornitz DM. Differential regulation of endochondral bone growth and joint development by FGFR1 and FGFR3 tyrosine kinase domains. Development. 2001;128(19):3867-76 PubMed: PMID11585811.
  34. Ornitz DM. Regulation of chondrocyte growth and differentiation by fibroblast growth factor receptor 3. Novartis Found Symp. 2001;232:63-76; discussion -80, 272-82.
  35. Henderson JE, Naski MC, Aarts MM, Wang D, Cheng L, Goltzman D, Ornitz DM. Expression of FGFR3 with the G380R achondroplasia mutation inhibits proliferation and maturation of CFK2 chondrocytic cells. J Bone Miner Res. 2000;15(1):155-65.
  36. McEwen DG, Green RP, Naski MC, Towler DA, Ornitz DM. Fibroblast growth factor receptor 3 gene transcription is suppressed by cyclic adenosine 3 ‘,5 ‘-monophosphate – Identification of a chondrocytic regulatory element. J Biol Chem. 1999;274(43):30934-42 PubMed: PMIDWOS:000083276700084.
  37. Naski MC, Ornitz DM. FGF signaling in skeletal development. Front Biosci. 1998;3:D781-94.
  38. Naski MC, Colvin JS, Coffin JD, Ornitz DM. Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. Development. 1998;125(24):4977-88 PubMed: PMID9811582.
  39. Naski MC, Wang Q, Xu J, Ornitz DM. Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia. Nat Genet. 1996;13(2):233-7 PubMed: PMID8640234.
  40. Colvin JS, Bohne BA, Harding GW, McEwen DG, Ornitz DM. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat Genet. 1996;12(4):390-7 PubMed: PMID8630492.