The Parathyroid Hormone/Parathyroid Hormone-Related Peptide Receptor Coordinates Endochondral Bone Development by Directly Controlling Chondrocyte Differentiation

During vertebrate limb development, growth plate chondrocytes undergo temporally and spatially coordinated differentiation that is necessary for proper morphogenesis. Parathyroid hormone-related peptide (PTHrP), its receptor, the PTH/PTHrP receptor, and Indian hedgehog are implicated in the regulati...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1998-10, Vol.95 (22), p.13030-13035
Main Authors: Chung, Ung-Il, Lanske, Beate, Lee, Kaechoong, Li, En, Kronenberg, Henry
Format: Article
Language:English
Subjects:
Animals
beta-Galactosidase - genetics
Biological Sciences
Biology
Blastocyst - physiology
Bones
Cell Differentiation
Cell growth
Cell lines
Cellular differentiation
Chimera
Chimeras
Chondrocytes
Crosses, Genetic
Embryonic and Fetal Development
Embryonic Induction
Embryos
Epiphyses
Female
Growth Plate - cytology
Growth Plate - embryology
Hedgehog Proteins
Hormones
Male
Mice
Mice, Inbred C57BL
Mice, Inbred Strains
Mice, Knockout
Mice, Transgenic
Osteogenesis
Parathyroid Hormone-Related Protein
Peptides
Proteins - genetics
Proteins - physiology
Rats
Receptor, Parathyroid Hormone, Type 1
Receptors
Receptors, Parathyroid Hormone - deficiency
Receptors, Parathyroid Hormone - genetics
Receptors, Parathyroid Hormone - physiology
Stem Cells
Trans-Activators
Transgenes
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Summary:During vertebrate limb development, growth plate chondrocytes undergo temporally and spatially coordinated differentiation that is necessary for proper morphogenesis. Parathyroid hormone-related peptide (PTHrP), its receptor, the PTH/PTHrP receptor, and Indian hedgehog are implicated in the regulation of chondrocyte differentiation, but the specific cellular targets of these molecules and specific cellular interactions involved have not been defined. Here we generated chimeric mice containing both wild-type and PTH/PTHrP receptor (-/-) cells, and analyzed cell-cell interactions in the growth plate in vivo. Abnormal differentiation of mutant cells shows that PTHrP directly signals to the PTH/PTHrP receptor on proliferating chondrocytes to slow their differentiation. The presence of ectopically differentiated mutant chondrocytes activates the Indian hedgehog/PTHrP axis and slows differentiation of wild-type chondrocytes. Moreover, abnormal chondrocyte differentiation affects mineralization of cartilaginous matrix in a non-cell autonomous fashion; matrix mineralization requires a critical mass of adjacent ectopic hypertrophic chondrocytes. Further, ectopic hypertrophic chondrocytes are associated with ectopic bone collars in adjacent perichondrium. Thus, the PTH/PTHrP receptor directly controls the pace and synchrony of chondrocyte differentiation and thereby coordinates development of the growth plate and adjacent bone.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.95.22.13030