Human Molecular Genetics Advance Access originally published online on December 17, 2003
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Human Molecular Genetics, 2004, Vol. 13, No. 3 271-284
DOI: 10.1093/hmg/ddh034
Defective bone mineralization and osteopenia in young adult FGFR3–/– mice
1Department of Medicine and 2Centre for Bone and Periodontal Research, McGill University, Montreal, Quebec, Canada, 3Division of Endocrinology, 4Division of Molecular Endocrinology and 5Calcium Research Laboratory, McGill University Health Centre, Royal Victoria Hospital, Montreal, Quebec, Canada and 6Washington University School of Medicine, St Louis, MO, USA
Received August 19, 2003; Accepted December 2, 2003
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.
* To whom correspondence should be addressed at: Centre for Bone and Periodontal Research, Royal Victoria Hospital, Room M11.41, 687 Pine Ave West, Montreal, QC, Canada H3A 1A1. Email: janet.henderson{at}mcgill.ca
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