Decreased c-Src Expression Enhances Osteoblast Differentiation and Bone Formation

doi:10.1083/jcb.151.2.311

Published online 18 October 2000. doi:10.1083/jcb.151.2.311

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© The Rockefeller University Press, 0021-9525/2000/10/311/ $5.00
The Journal of Cell Biology, Volume 151, Number 2, October 16, 2000 311-320

Original Article

Decreased c-Src Expression Enhances Osteoblast Differentiation and Bone Formation

Marilena Marzia^a,b, Natalie A. Sims^h, Susanne Voit^d, Silvia Migliaccio^a,c,d, Anna Taranta^a,e, Silvia Bernardini^e, Tullio Faraggiana^b, Toshiyuki Yoneda^f, Gregory R. Mundy^f, Brendan F. Boyce^g, Roland Baron^h, and Anna Teti^d
^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

Correspondence to: Anna Teti, Department of Experimental Medicine, University of L'Aquila, Via Vetoio-Coppito 2, 67100 L'Aquila, Italy. Tel:39-0862-433510 Fax:39-0862-433523

c-src deletion in mice leads to osteopetrosis as a result ofreduced bone resorption due to an alteration of the osteoclast.We report that deletion/reduction of Src expression enhancesosteoblast differentiation and bone formation, contributingto the increase in bone mass. Bone histomorphometry showed thatbone formation was increased in Src null compared with wild-typemice. In vitro, alkaline phosphatase (ALP) activity and nodulemineralization were increased in primary calvarial cells andin SV40-immortalized osteoblasts from Src^-/- relative to Src^+/+mice. Src-antisense oligodeoxynucleotides (AS-src) reduced Srclevels by $~$ 60% and caused a similar increase in ALP activityand nodule mineralization in primary osteoblasts in vitro. Reductionin cell proliferation was observed in primary and immortalizedSrc^-/- osteoblasts and in normal osteoblasts incubated withthe AS-src. Semiquantitative reverse transcriptase-PCR revealedupregulation of ALP, Osf2/Cbfa1 transcription factor, PTH/PTHrPreceptor, osteocalcin, and pro-alpha 2(I) collagen in Src-deficientosteoblasts. The expression of the bone matrix protein osteopontinremained unchanged. Based on these results, we conclude thatthe 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 developmentof the osteopetrotic phenotype in Src-deficient mice.

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

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