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© The Rockefeller University Press, 0021-9525/1998//295 $5.00
The Journal of Cell Biology, Volume 142, Number 1, , 1998 295-305

Differential Roles for Bone Morphogenetic Protein (BMP) Receptor Type IB and IA in Differentiation and Specification of Mesenchymal Precursor Cells to Osteoblast and Adipocyte Lineages

D. Chen^*, X. Ji^*, M.A. Harris^*, J.Q. Feng^*, G. Karsenty, A.J. Celeste, V. Rosen, G.R. Mundy^*, and S.E. Harris^*

^* Department of Medicine, Division of Endocrinology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030; and Genetics Institute, Cambridge, Massachusetts 02140

Cumulative evidence indicates that osteoblasts and adipocytes share a common mesenchymal precursor and that bone morphogenetic proteins (BMPs) can induce both osteoblast and adipocyte differentiation of this precursor. In the present study, we investigated the roles of BMP receptors in differentiation along these separate lineages using a well-characterized clonal cell line, 2T3, derived from the mouse calvariae. BMP-2 induced 2T3 cells to differentiate into mature osteoblasts or adipocytes depending upon culture conditions. To test the specific roles of the type IA and IB BMP receptor components, truncated and constitutively active type IA and IB BMP receptor cDNAs were stably expressed in these cells. Overexpression of truncated type IB BMP receptor (trBMPR-IB) in 2T3 cells completely blocked BMP-2–induced osteoblast differentiation and mineralized bone matrix formation. Expression of trBMPR-IB also blocked mRNA expression of the osteoblast specific transcription factor, Osf2/ Cbfa1, and the osteoblast differentiation-related genes, alkaline phosphatase (ALP) and osteocalcin (OC). BMP-2–induced ALP activity could be rescued by transfection of wild-type (wt) BMPR-IB into 2T3 clones containing trBMPR-IB. Expression of a constitutively active BMPR-IB (caBMPR-IB) induced formation of mineralized bone matrix by 2T3 cells without addition of BMP-2. In contrast, overexpression of trBMPR-IA blocked adipocyte differentiation and expression of caBMPR-IA induced adipocyte formation in 2T3 cells. Expression of the adipocyte differentiation-related genes, adipsin and PPAR, correlated with the distinct phenotypic changes found after overexpression of the appropriate mutant receptors. These results demonstrate that type IB and IA BMP receptors transmit different signals to bone-derived mesenchymal progenitors and play critical roles in both the specification and differentiation of osteoblasts and adipocytes.

Key Words: 2T3 cells • BMP signaling • commitment • mineralization • Osf2/cbfal

Abbreviations used in this paper: MEM, minimal essential medium; aa, amino acids; ALP, alkaline phosphatase; BMP, bone morphogenic protein; caBMPR-IB, constitutively active type IB BMP receptor; FRC, fetal rat calvarial; HA, hemagglutinin; IBMX, 3-isobutyl-1-methyl xanthine; OC, osteocalcin; RT, reverse transcription; trBMPR-IB, truncated type IB BMP receptor; wt, wild-type.

We would like to acknowledge M. Dallas and D. Guerro (University of Texas Health Science Center at San Antonio, TX) for the quantitation of mineralized bone matrix formation and assistance with the electron microscopy. We thank J. Wrana (The Hospital for Sick Children, Toronto, Canada) for BMPR-IB and constitutively active BMPR-IA and BMPR-IB cDNA constructs and J. Massagué (Memorial Sloan-Kettering Cancer Center, New York) and B. Spiegelman (Harvard Medical School, Boston, MA) for BMPR-II and PPAR cDNA probe. We are grateful to N. Garrett for her help with the preparation of this manuscript. We also wish to thank L. Bonewald (both from University of Texas Health Science Center at San Antonio) for her comments on the manuscript.

Address all correspondence to S.E. Harris, Medicine/Endocrinology, 7703 Floyd Curl Drive, San Antonio, TX 78284-7877. Tel.: (210) 567-4900. Fax: (210) 567-6693. E-mail: harris{at}uthscsa.edu

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