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© The Rockefeller University Press, 0021-9525/1999//783 $5.00
The Journal of Cell Biology, Volume 145, Number 4, , 1999 783-794

Parathyroid Hormone–related Peptide (PTHrP)-dependent and -independent Effects of Transforming Growth Factor β (TGF-β) on Endochondral Bone Formation

Rosa Serra^*, Andrew Karaplis, and Philip Sohn^*

^* Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and Department of Medicine, Division of Endocrinology, Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec H3T 1E2, Canada

Previously, we showed that expression of a dominant-negative form of the transforming growth factor β (TGF-β) type II receptor in skeletal tissue resulted in increased hypertrophic differentiation in growth plate and articular chondrocytes, suggesting a role for TGF-β in limiting terminal differentiation in vivo. Parathyroid hormone–related peptide (PTHrP) has also been demonstrated to regulate chondrocyte differentiation in vivo. Mice with targeted deletion of the PTHrP gene demonstrate increased endochondral bone formation, and misexpression of PTHrP in cartilage results in delayed bone formation due to slowed conversion of proliferative chondrocytes into hypertrophic chondrocytes. Since the development of skeletal elements requires the coordination of signals from several sources, this report tests the hypothesis that TGF-β and PTHrP act in a common signal cascade to regulate endochondral bone formation. Mouse embryonic metatarsal bone rudiments grown in organ culture were used to demonstrate that TGF-β inhibits several stages of endochondral bone formation, including chondrocyte proliferation, hypertrophic differentiation, and matrix mineralization. Treatment with TGF-β1 also stimulated the expression of PTHrP mRNA. PTHrP added to cultures inhibited hypertrophic differentiation and matrix mineralization but did not affect cell proliferation. Furthermore, terminal differentiation was not inhibited by TGF-β in metatarsal rudiments from PTHrP-null embryos; however, growth and matrix mineralization were still inhibited. The data support the model that TGF-β acts upstream of PTHrP to regulate the rate of hypertrophic differentiation and suggest that TGF-β has both PTHrP-dependent and PTHrP-independent effects on endochondral bone formation.

Key Words: chondrocyte differentiation • skeletal development • perichondrium • organ culture • transforming growth factor β receptors

Abbreviations used in this paper: BMP, bone morphogenic protein; BrdU, bromo deoxyuridine; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; Hh, hedgehog; Ihh, Indian hedgehog; p.c., post coitum; PTH, parathyroid hormone; PTHrP, PTH-related peptide; RT, reverse transcription.

Address correspondence before June 1, 1999, to Rosa Serra, Department of Cell Biology, 649 MRBII, Vanderbilt Cancer Center, Nashville, TN 37232-3868. Tel.: (615) 936-1507. Fax: (615) 936-1790. After June 1, 1999, R. Serra's address will be Department of Cellular and Molecular Physiology, University of Cincinnati School of Medicine, 231 Bethesda, Rm. 4251, Cincinnati, OH 45267. Fax: (513) 558-5738.

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