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J Biol Chem, Vol. 275, Issue 2, 969-976, January 14, 2000

Targeted Inhibition of Osteopontin Expression in the Mammary Gland Causes Abnormal Morphogenesis and Lactation Deficiency*

Mohamed NemirDagger §, Dibyendu BhattacharyyaDagger §, Xiaoming LiDagger , Krishna SinghDagger , Anil B. Mukherjeepar , and Barid B. MukherjeeDagger **Dagger Dagger

From the Departments of Dagger  Biology and ** Human Genetics, McGill University, Montreal, Quebec H3A 1B1, Canada and the par  Section on Developmental Genetics, Heritable Disorders Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892-1830

Osteopontin (OPN) is a sialic acid-rich, adhesive, extracellular matrix (ECM) protein with Arg-Gly-Asp cell-binding sequence that interacts with several integrins, including alpha vbeta 3. Since the ECM is a key regulator of mammary gland morphogenesis, and mammary epithelial cells express OPN at elevated levels, we sought to determine whether this protein plays a role in the postnatal mammary gland development. By generating transgenic mice that express OPN antisense-RNA (AS-OPN mice) in the mammary epithelia we achieved suppression of OPN production in this organ. The pregnant AS-OPN mice displayed a lack of mammary alveolar structures, a drastic reduction in the synthesis of beta -casein, whey acidic milk protein, and lactation deficiency. In agreement with these findings, we uncovered that a mammary cell line, NMuMG, which undergoes both structural and functional differentiation on ECM-coated plates, when transfected with an antisense OPN-cDNA construct, failed to undergo such differentiation. Furthermore, the results of gel-invasion assays demonstrated that these cells manifest elevated matrix metalloproteinase (MMP) activity when OPN expression is significantly reduced. The identity of this proteinase as MMP-2 is confirmed by Western blotting, zymography, and inhibition of its activity by a specific inhibitor, TIMP-2. Taken together, our results demonstrate, for the first time, an essential role of OPN in mammary gland differentiation and that the molecular mechanism(s) of its action, at least in part, involves down-regulation of MMP-2.

* This work was supported by a grant from the March of Dimes Birth Defects Foundation (to B. B. M.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors contributed equally to this work.

Present address: Myocardial Biology Unit, Dept. of Medicine, Boston University Medical Center, Boston, MA 02138.

Dagger Dagger To whom all correspondence should be addressed: Dept. of Biology, McGill University, 1205 Dr. Penfield Ave., Montreal, Quebec H3A 1B1, Canada. Tel.: 514-398-3749; Fax: 514-398-5069; E-mail: baridm@ bio1.lan.mcgill.ca.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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