Defective bone mineralization and osteopenia in young adult FGFR3-/- mice.
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.
Valverde-Franco
Gladys
G
Department of Medicine and Centre for Bone and Periodontal Research, McGill University, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1.
Liu
Hanlong
H
Davidson
David
D
Chai
Sen
S
Valderrama-Carvajal
Hector
H
Goltzman
David
D
Ornitz
David M
DM
Henderson
Janet E
JE
D000818:Animals; D001851:Bone Diseases, Metabolic / Q000235:genetics* / Q000378:metabolism; D002113:Calcification, Physiologic / Q000235:genetics* / Q000502:physiology; D005269:Femur / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D011859:Radiography; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism; D013977:Tibia / Q000378:metabolism / Q000473:pathology
D017468:Receptors, Fibroblast Growth Factor; C496366:Fgfr3 protein, mouse; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3