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© The Rockefeller University Press, 0021-9525/2000//311 $5.00
The Journal of Cell Biology, Volume 151, Number 2, , 2000 311-320

Decreased C-Src Expression Enhances Osteoblast Differentiation and Bone Formation

^a Department of Histology and General Embryology, University La Sapienza, 00161 Rome, Italy
^b Department of Experimental Medicine, University La Sapienza, 00161 Rome, Italy
^c Department of Medical Physiopathology, University La Sapienza, 00161 Rome, Italy
^d Department of Experimental Medicine, University of L'Aquila, 00161 L'Aquila, Italy
^e Istituto Dermopatico dell'Immacolata, 00167 Rome, Italy
^f Division of Endocrinology and Metabolism, University of Texas Health Science Center, San Antonio, Texas 78284-7877
^g Department of Pathology, University of Texas Health Science Center, San Antonio, Texas 78284-7877
^h Departments of Orthopaedics and of Cell Biology, Yale University, New Haven, Connecticut 06510
Department of Experimental Medicine, University of L'Aquila, Via Vetoio-Coppito 2, 67100 L'Aquila, Italy.39-0862-43352339-0862-433510

c-src deletion in mice leads to osteopetrosis as a result of reduced bone resorption due to an alteration of the osteoclast. We report that deletion/reduction of Src expression enhances osteoblast differentiation and bone formation, contributing to the increase in bone mass. Bone histomorphometry showed that bone formation was increased in Src null compared with wild-type mice. In vitro, alkaline phosphatase (ALP) activity and nodule mineralization were increased in primary calvarial cells and in SV40-immortalized osteoblasts from Src^–/– relative to Src^+/+ mice. Src-antisense oligodeoxynucleotides (AS-src) reduced Src levels by 60% and caused a similar increase in ALP activity and nodule mineralization in primary osteoblasts in vitro. Reduction in cell proliferation was observed in primary and immortalized Src^–/– osteoblasts and in normal osteoblasts incubated with the AS-src. Semiquantitative reverse transcriptase-PCR revealed upregulation of ALP, Osf2/Cbfa1 transcription factor, PTH/PTHrP receptor, osteocalcin, and pro-alpha 2(I) collagen in Src-deficient osteoblasts. The expression of the bone matrix protein osteopontin remained unchanged. Based on these results, we conclude that the reduction of Src expression not only inhibits bone resorption, but also stimulates osteoblast differentiation and bone formation, suggesting that the osteogenic cells may contribute to the development of the osteopetrotic phenotype in Src-deficient mice.

Key Words: osteopetrosis • Src • osteoblast • differentiation • bone formation

© 2000 The Rockefeller University Press

B.F. Boyce's present address is Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14610.

Abbreviations used in this paper: ALP, alkaline phosphatase; AS-src, Src-antisense oligodeoxynucleotide; COL1A2, pro-alpha 2(I) collagen; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; OCN, osteocalcin; ODN, oligodeoxynucleotide; PTH/PTHrP, parathyroid hormone/parathyroid hormone related peptide; RT, reverse transcriptase; S-src, Src-sense oligodeoxynucleotide; Src, sarcoma.

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