Activated parathyroid hormone/parathyroid hormone–related protein receptor in osteoblastic cells differentially affects cortical and trabecular bone
L.M. Calvi, … , R. Baron, E. Schipani
L.M. Calvi, … , R. Baron, E. Schipani
Published February 1, 2001
Citation Information: J Clin Invest. 2001;107(3):277-286. https://doi.org/10.1172/JCI11296.
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Article

Activated parathyroid hormone/parathyroid hormone–related protein receptor in osteoblastic cells differentially affects cortical and trabecular bone

Abstract

Parathyroid hormone (PTH), an important regulator of calcium homeostasis, targets most of its complex actions in bone to cells of the osteoblast lineage. Furthermore, PTH is known to stimulate osteoclastogenesis indirectly through activation of osteoblastic cells. To assess the role of the PTH/PTH-related protein receptor (PPR) in mediating the diverse actions of PTH on bone in vivo, we generated mice that express, in cells of the osteoblastic lineage, one of the constitutively active receptors described in Jansen’s metaphyseal chondrodysplasia. In these transgenic mice, osteoblastic function was increased in the trabecular and endosteal compartments, whereas it was decreased in the periosteum. In trabecular bone of the transgenic mice, there was an increase in osteoblast precursors, as well as in mature osteoblasts. Osteoblastic expression of the constitutively active PPR induced a dramatic increase in osteoclast number in both trabecular and compact bone in transgenic animals. The net effect of these actions was a substantial increase in trabecular bone volume and a decrease in cortical bone thickness of the long bones. These findings, for the first time to our knowledge, identify the PPR as a crucial mediator of both bone-forming and bone-resorbing actions of PTH, and they underline the complexity and heterogeneity of the osteoblast population and/or their regulatory microenvironment.

Authors

L.M. Calvi, N.A. Sims, J.L. Hunzelman, M.C. Knight, A. Giovannetti, J.M. Saxton, H.M. Kronenberg, R. Baron, E. Schipani

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Figure 1

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Transgene construct and its expression. (a) Shown is the scheme of the t...
Transgene construct and its expression. (a) Shown is the scheme of the transgene construct with the location of probes A and B for Southern blot analysis of genomic DNA. Locations of the translation initiation codon (ATG), the receptor mutation (H223R), and the stop codon (Stop) in the cDNA encoding the human PPR mutant, HKrk-H223R, are seen. Restriction sites for the enzymes HindIII, PvuII, and ScaI are also indicated. Oligonucleotide S was used as probe for Southern blot analysis of RT-PCR products, oligonucleotides S1 and A were used for RT-PCR of total RNA, and oligonucleotides S2 and A1 were used to generate the DT7 probe. (b) Southern blot analysis of the RT-PCR products with probe S: RT-PCR products from line not expressing the transgene (lanes 1 and 6), CL1 (lanes 2, 3, 7, and 8), and CL2 (lanes 4 and 9), with negative control in lane 5 and –RT controls in lanes 6–9. (c–h) In situ hybridization with the 35S-labeled DT7 cRNA in serial section of decalcified proximal tibia of newborn CL2 mouse (c and d),and a wild-type littermate (g and h). In the high-magnification images from 2-week-old CL2 mutant (e and f), the arrow indicates the periosteal surface. (i) In situ hybridization with the 35S-labeled PPR cRNA in a section of decalcified proximal tibia of a newborn wild-type mouse. All sections were counterstained with hematoxylin and eosin; bright-field (c, e, g) and dark-field (d, f, h, i) views are shown.