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

• Published in: Human molecular genetics 2004-02, Vol.13 (3), p.271-284
• Main Authors: Valverde-Franco, Gladys, Liu, Hanlong, Davidson, David, Chai, Sen, Valderrama-Carvajal, Hector, Goltzman, David, Ornitz, David M., Henderson, Janet E.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Bone Diseases, Metabolic - genetics; Bone Diseases, Metabolic - metabolism; Calcification, Physiologic - genetics; Calcification, Physiologic - physiology; Classical genetics, quantitative genetics, hybrids; Diseases of the osteoarticular system; Femur - diagnostic imaging; Femur - metabolism; Femur - pathology; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Human; Medical sciences; Mice; Molecular and cellular biology; Osteoporosis. Osteomalacia. Paget disease; Protein-Tyrosine Kinases - deficiency; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Radiography; Receptor, Fibroblast Growth Factor, Type 3; Receptors, Fibroblast Growth Factor - deficiency; Receptors, Fibroblast Growth Factor - genetics; Receptors, Fibroblast Growth Factor - metabolism; Stromal Cells - metabolism; Tibia - metabolism; Tibia - pathology
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddh034

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.