Defective bone mineralization and osteopenia in young adult FGFR3 -/- mice

Gladys Valverde-Franco, Hanlong Liu, David Davidson, Sen Chai, Hector Valderrama-Carvajal, David Goltzman, David M. Ornitz, Janet E. Henderson

Research output: Contribution to journalArticlepeer-review

111 Scopus citations

Abstract

Mutations that cause constitutive activation of fibroblast growth factor receptor 3 (FGFR3) result in skeletal disorders that are characterized by short-limbed dwarfism and premature closure of cranial sutures. In previous work, it was shown that congenital deficiency of FGFR3 led to skeletal overgrowth. Using a combination of imaging, classic histology and molecular cell biology we now show that young adult FGFR3-/- mice are osteopenic due to reduced cortical bone thickness and defective trabecular bone mineralization. The reduction in mineralized bone and lack of trabecular connectivity observed by micro-computed tomography were confirmed in histological and histomorphometric analyses, which revealed a significant decrease in calcein labelling of mineralizing surfaces and a significant increase in osteoid in the long bones of 4-month-old FGFR3-/- mice. These alterations were associated with increased staining for recognized markers of differentiated osteoblasts and increased numbers of tartrate-resistant acid phsophatase postitive osteoclasts. Primary cultures of adherent bone marrow-derived cells from FGFR3-/- mice expressed markers of differentiated osteoblasts but developed fewer mineralized nodules than FGFR3+/+ cultures of the same age. Our observations reveal a role for FGFR3 in post-natal bone growth and remodelling, which identifies it as a potential therapeutic target for osteopenic disorders and those associated with defective bone mineralization.

Original languageEnglish
Pages (from-to)271-284
Number of pages14
JournalHuman molecular genetics
Volume13
Issue number3
DOIs
StatePublished - Feb 1 2004

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