Haploinsufficiency of Parathyroid Hormone-Related Peptide (PTHrP) Results in Abnormal Postnatal Bone Development

Abstract

Although apparently phenotypically normal at birth, mice heterozygous for inactivation of the gene encoding parathyroid hormone-related peptide (PTHrP) develop haplotype insufficiency by 3 months of age. In addition to histologic and morphologic abnormalities similar to those seen in homozygous mutants, heterozygous animals demonstrated alterations in trabecular bone and bone marrow. These included metaphyseal bone spicules which were diminished in volume, irregularly distributed, and less well developed than those seen in age-matched controls as well as bone marrow, which contained an inordinate number of adipocytes. A substantial reduction in PTHrP mRNA was detected in heterozygous tissue, while circulating parathyroid hormone (PTH) and calcium concentrations were normal. Thus, while a physiologic concentration of PTH was capable of maintaining calcium homeostasis, it was incapable of compensating for PTHrP haploinsufficiency in developing bone. In normal animals, both PTHrP and the PTH/PTHrP receptor were expressed predominantly in chondrocytes situated throughout the proliferative zone of the tibial growth plate. In the metaphysis, the PTH/PTHrP receptor was identified on osteoblasts and preosteoblastic cells situated in the bone marrow, while PTHrP was expressed only by osteoblasts. These observations indicate that postnatal bone development involves susceptible pathways that display exquisite sensitivity to critical levels of PTHrP and imply that the skeletal effects of PTH are influenced by locally produced PTHrP. Moreover, identification of both the ligand and its N-terminal receptor in metaphyseal osteoblasts and their progenitors suggests an autocrine/paracrine role for the protein in osteoblast differentiation and/or function. Impairment in this function as a consequence of PTHrP haploinsufficiency may critically influence the course of bone formation, resulting in altered trabecular architecture and perhaps low bone mass and increased bone fragility.

The N- and C-terminal domains of parathyroid hormone-related protein affect differently the osteogenic and adipogenic potential of human mesenchymal stem cells

“…Related to these in vitro data, a decrease in the expression of adipogenic genes in bone were found in osteopenic rats after daily administration of PTH (1-34) (Kulkarni et al, 2007). Furthermore, mice with heterozygous inactivation of the PTHrP gene have been shown to display low bone mass associated with increased bone marrow adipocytes (Amizuka et al, 1996). However, this increased bone marrow adiposity was absent in osteopenic mice with osteoblast-specific targeted disruption of PTHrP by using Cre/lox technology, which was thought to be accounted for by the timing of PTHrP ablation relative to the osteogenic and adipocytic programs (Miao et al, 2005).…”

The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition

“…Another transcription factor, Atf4 regulates bone matrix deposition by mature osteoblasts [25]. Furthermore, several signaling pathways have been shown to regulate postnatal osteoblast function including Ihh [26], Wnt/Lrp5 [27], TGFb-BMP/Smads [28][29][30], BMP/MEKK2/MEK5-7/Jnk [31], b-adrenergic [32], IGF-1 [16], insulin [33] and PTH signaling [34]. The p38 MAPK pathway has been recently shown to be an essential regulator of osteoblastogenesis during skeletogenesis [12,13].…”

Ossification of the mouse metatarsal: Differentiation and proliferation in the presence/absence of a defined growth plate

“…In addition, mice with ablated PTHrP or PTH/PTHrP receptor (PPR) genes have shortened, disorganized growth plates in the embryonic skele-ton as a consequence of accelerated differentiation of their columnar chondrocytes (Amizuka et al, 1994;Lanske et al, 1996). Mice haploinsufficient for PTHrP (Amizuka et al, 1996) have smaller epiphyses and growth plates. In particular, the columnar zones are shortened and manifest disorganized longitudinal columns that result in trabecular spicules with reduced linear organization compared to controls.…”