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J. Biol. Chem., Vol. 281, Issue 14, 9576-9588, April 7, 2006

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Up-regulation of the Wnt, Estrogen Receptor, Insulin-like Growth Factor-I, and Bone Morphogenetic Protein Pathways in C57BL/6J Osteoblasts as Opposed to C3H/HeJ Osteoblasts in Part Contributes to the Differential Anabolic Response to Fluid Shear^*

From the Musculoskeletal Disease Center, Jerry L. Pettis Memorial Veterans Affairs Medical Center, and the Department of Medicine, Loma Linda University, Loma Linda, California 92357

C57BL/6J (B6), but not C3H/HeJ (C3H), mice responded to mechanical loading with an increase in bone formation. A 30-min steady fluid shear of 20 dynes/cm² increased [³H]thymidine incorporation and alkaline phosphatase activity and up-regulated the expression of early mechanoresponsive genes (integrin 1 (Igtb1) and cyclooxygenase-2 (Cox-2)) in B6 but not C3H osteoblasts, indicating that the differential mechanosensitivity was intrinsic to osteoblasts. In-house microarray analysis with 5,500 gene fragments revealed that the expression of 669 genes in B6 osteoblasts and 474 genes in C3H osteoblasts was altered 4 h after the fluid shear. Several genes associated with the insulin-like growth factor (IGF)-I, the estrogen receptor (ER), the bone morphogenetic protein (BMP)/transforming growth factor-, and Wnt pathways were differentially up-regulated in B6 osteoblasts. In vitro mechanical loading also led to up-regulation of these genes in the bones of B6 but not C3H mice. Pretreatment of B6 osteoblasts with inhibitors of the Wnt pathway (endostatin), the BMP pathway (Noggin), or the ER pathway (ICI182780) blocked the fluid shear-induced proliferation. Inhibition of integrin and Cox-2 activation by echistatin and indomethacin, respectively, each blocked the fluid shear-induced up-regulation of genes associated with these four pathways. In summary, up-regulation of the IGF-I, ER, BMP, and Wnt pathways is involved in mechanotransduction. These four pathways are downstream to the early mechanoresponsive genes, i.e. Igtb1 and Cox-2. In conclusion, differential up-regulation of these anabolic pathways may in part contribute to the good and poor response, respectively, in the B6 and C3H mice to mechanical loading.

Received for publication, August 22, 2005 , and in revised form, January 13, 2006.

^* This work was supported in part by a special appropriation to the Jerry L. Pettis Memorial Veterans Affairs Medical Center, Musculoskeletal Disease Center, and by a Merit Review provided by the Office of Research and Development, Medical Research Service, Department of Veteran Affairs, and in part by Assistance Award DAMD17-01-1-0744 provided by The United States Army Medical Research Acquisition Activity (Fort Detrick MD 21702-5014). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1-3.

¹ To whom correspondence should be addressed: Musculoskeletal Disease Center (151), Jerry L. Pettis Memorial Veterans Affairs Medical Center, 11201 Benton St., Loma Linda, CA 92357. Tel.: 909-825-7084 (ext. 2836); Fax: 909-796-1680; E-mail: William.Lau{at}med.va.gov.

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