Inhibition of terminal chondrocyte differentiation by bone morphogenetic protein 7 (OP-1) in vitro depends on the periarticular region but is independent of parathyroid hormone-related peptide

Bone morphogenetic protein-7, or BMP-7 (OP-l), is highly expressed in the p erichondrium of embryonic long bones and is thought to play a role in endoc hondral ossification. Previously we have shown that BMP-7 inhibits terminal chondrocyte differentiation; that is, chondrocyte hypertrophy and minerali zation in cultured explants of embryonic mouse metatarsals. However, the me chanism of this inhibition and the target cells of BMP-7 are still unknown, In this study we show that BMP-7 inhibits terminal chondrocyte differentia tion indirectly, via an interaction with the periarticular region of the ex plants, This region also expresses parathyroid hormone-related peptide (PTH rP), PTHrP regulates terminal chondrocyte differentiation by inhibiting hyp ertrophic differentiation of prehypertrophic chondrocytes, The differentiat ing center in turn regulates PTHrP expression via a feedback loop involving Indian hedgehog (Ihh), which is expressed in the prehypertrophic chondrocy tes, Ihh is thought to act on perichondrial cells, which in turn start to e xpress an as yet unknown mediator that stimulates PTHrP expression in the p eriarticular region, It has been suggested that this factor belongs to the BMP-family, We investigated whether the inhibition of terminal chondrocyte differentiation by BMP-7 was due to upregulation of the PTHrP-Ihh feedback loop and whether BMP-7 was the unknown factor in the loop. Here we show tha t exogeneous BMF-7 did not upregulate the mRNA expression of PTHrP, Ihh, or the PTH/PTHrP receptor in cultured wild-type embryonic metatarsals, Furthe rmore, BMP-7 could still inhibit terminal chondrocyte differentiation in th e metatarsals of PTHrP-deficient (PTHrP-/-) mouse embryos, These data indic ate that the BMP-7-mediated inhibition of terminal chondrocyte differentiat ion in vitro is independent of the PTHrP-Ihh feedback loop. We concluded th at BMP-7 modulates terminal chondrocyte differentiation and cartilage miner alization of fetal bone explants in vitro via as yet unknown inhibitory fac tor(s) produced in the periarticular region, (C) 1999 by Elsevier Science I nc. All rights reserved.