Osteocyte death, one of the hallmarks of skeletal aging, contributes to the age-related decline in bone strength and the increase in age-related fractures. In addition to aging, many other factors also lead to osteocyte death, including unloading, sex hormone deficiency, glucocorticoid excess, inflammation, and osteoarthritis. Although osteocytes function as master regulators of bone remodeling, the underlying molecular mechanisms that sustain osteocyte viability are poorly understood.
We are studying a novel role for Fibroblast Growth Factor Receptor (FGFR) signaling in the maintenance of osteocyte viability and skeletal homeostasis. In a recent publication, we identified a novel requirement for FGFR signaling for osteocyte survival. We showed that conditional knockout of FGFRs in mature osteoblasts and osteocytes led to osteocyte death in juvenile (3-week-old) mice and secondarily, increased bone mass as these mice aged. We then temporally inactivated FGFRs in osteoblasts and osteocytes in adult (12-week-old) mice to bypass any effects on developing or actively growing bone. This also resulted in osteocyte death after several weeks and increased bone mass after several months.
Ongoing studies address the mechanisms by which FGFR signaling maintains osteocyte viability and skeletal homeostasis in adult mice. We are using lineage tracing, anabolic loading, and single-cell mRNA sequencing to determine whether existing osteocytes vs. newly formed osteocytes are sensitive to loss of FGFR signaling. We will also determine whether FDA-approved FGFR inhibitors (Erdafitinib, Pemigatinib) could affect bone homeostasis and whether activation of FGFR signaling in mature osteoblasts and osteocytes is protective under conditions that promote osteocyte death.
Bone Biology publications:
1. Ornitz, D.M., and Marie, P.J. (2015). Fibroblast growth factor signaling in skeletal development and disease. Genes Dev 29, 1463-1486. 10.1101/gad.266551.115.
2. Hung, I.H., Schoenwolf, G.C., Lewandoski, M., and Ornitz, D.M. (2016). A combined series of Fgf9 and Fgf18 mutant alleles identifies unique and redundant roles in skeletal development. Dev Biol 411, 72-84. 10.1016/j.ydbio.2016.01.008.
3. Karuppaiah, K., Yu, K., Lim, J., Chen, J., Smith, C., Long, F., and Ornitz, D.M. (2016). FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth. Development 143, 1811-1822. 10.1242/dev.131722.
4. Ornitz, D.M., and Legeai-Mallet, L. (2017). Achondroplasia: Development, pathogenesis, and therapy. Dev Dyn 246, 291-309. 10.1002/dvdy.24479.
5. McKenzie, J., Smith, C., Karuppaiah, K., Langberg, J., Silva, M.J., and Ornitz, D.M. (2019). Osteocyte Death and Bone Overgrowth in Mice Lacking Fibroblast Growth Factor Receptors 1 and 2 in Mature Osteoblasts and Osteocytes. J Bone Miner Res 34, 1660-1675. 10.1002/jbmr.3742.
6. Ornitz, D.M., and Marie, P.J. (2019). Fibroblast growth factors in skeletal development. Curr Top Dev Biol 133, 195-234. 10.1016/bs.ctdb.2018.11.020.
7. Yang, L.M., and Ornitz, D.M. (2019). Sculpting the skull through neurosensory epithelial-mesenchymal signaling. Dev Dyn 248, 88-97. 10.1002/dvdy.24664.
8. Ganji, E., Leek, C., Duncan, W., Patra, D., Ornitz, D.M., and Killian, M.L. (2023). Targeted deletion of Fgf9 in tendon disrupts mineralization of the developing enthesis. FASEB J 37, e22777. 10.1096/fj.202201614R.
9. Wernle, K.K., Sonnenfelt, M.A., Leek, C.C., Ganji, E., Sullivan, A.L., Offutt, C., Shuff, J., Ornitz, D.M., and Killian, M.L. (2023). Loss of Fgfr1 and Fgfr2 in Scleraxis-lineage cells leads to enlarged bone eminences and attachment cell death. Dev Dyn 252, 1180-1188. 10.1002/dvdy.600.
10. Bodmer, N.K., Knutsen, R.H., Roth, R.A., Castile, R.M., Brodt, M.D., Gierasch, C.M., Broekelmann, T.J., Gibson, M.A., Haspel, J.A., Lake, S.P., et al. (2024). Multi-organ phenotypes in mice lacking latent TGFbeta binding protein 2 (LTBP2). Dev Dyn 253, 233-254. 10.1002/dvdy.651.