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First published online 24 July 2007
doi: 10.1242/jcs.003855

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Osteopenia, decreased bone formation and impaired osteoblast development in Sox4 heterozygous mice

Lise Sofie Haug Nissen-Meyer^1,*, Rune Jemtland², Vigdis T. Gautvik¹, Mona E. Pedersen¹, Rita Paro^1,, Dario Fortunati¹, Dominique D. Pierroz³, Vincent A. Stadelmann⁴, Sjur Reppe¹, Finn P. Reinholt⁵, Andrea Del Fattore⁶, Nadia Rucci⁶, Anna Teti⁶, Serge Ferrari³ and Kaare M. Gautvik^1,7,

¹ Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway
² Endocrine Section, Department of Medicine, University of Oslo, Rikshospitalet-Radiumhospitalet Medical Centre, N-0027 Oslo, Norway
³ Service of Bone Diseases, WHO Collaborating Center for Osteoporosis Prevention, Geneva University Hospital, 1211 Geneva, Switzerland
⁴ Laboratory of Biomechanical Orthopedics, EPFL-HOSR, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
⁵ Institute of Pathology, University of Oslo, and The Pathology Clinic, Rikshospitalet-Radiumhospitalet Medical Centre, N-0027 Oslo, Norway
⁶ Department of Experimental Medicine, University of L'Aquila, 67100 L'Aquila, Italy
⁷ Department of Clinical Chemistry, Ullevål University Hospital, N-0407 Oslo, Norway

Author for correspondence (e-mail: k.m.gautvik{at}medisin.uio.no)

Accepted 11 June 2007

The transcription factor Sox4 is vital for fetal development, as Sox4^–/– homozygotes die in utero. Sox4 mRNA is expressed in the early embryonic growth plate and is regulated by parathyroid hormone, but its function in bone modeling/remodeling is unknown. We report that Sox4^+/– mice exhibit significantly lower bone mass (by dual-energy X-ray absorptiometry) from an early age, and fail to obtain the peak bone mass of wild-type (WT) animals. Microcomputed tomography (µCT), histomorphometry and biomechanical testing of Sox4^+/– bones show reduced trabecular and cortical thickness, growth plate width, ultimate force and stiffness compared with WT. Bone formation rate (BFR) in 3-month-old Sox4^+/– mice is 64% lower than in WT. Primary calvarial osteoblasts from Sox4^+/– mice demonstrate markedly inhibited proliferation, differentiation and mineralization. In these cultures, osterix (Osx) and osteocalcin (OCN) mRNA expression was reduced, whereas Runx2 mRNA was unaffected. No functional defects were found in osteoclasts. Silencing of Sox4 by siRNA in WT osteoblasts replicated the defects observed in Sox4^+/– cells. We demonstrate inhibited formation and altered microarchitecture of bone in Sox4^+/– mice versus WT, without apparent defects in bone resorption. Our results implicate the transcription factor Sox4 in regulation of bone formation, by acting upstream of Osx and independent of Runx2.

Key words: Sox4, Bone density, Bone biomechanics, Bone formation rate, Osteoblast cultures, Osteoblast function

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