IGF-I Receptor Is Required for the Anabolic Actions of Parathyroid Hormone on Bone

Wang, Yongmei; Nishida, Shigeki; Boudignon, Benjamin; Burghardt, Andrew J.; Elalieh, Hashem; Hamilton, Michelle M.; Majumdar, Sharmila; Halloran, Bernard P.; Clemens, Thomas L.; Bikle, Daniel D.

doi:10.1359/jbmr.070517

Cited by 135 publications

(140 citation statements)

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“…Given that PTH has a direct effect on the activity of the osteoblast, a cell known to have the PTHR (Halloran et al 1997), and that IGF1 is required for the skeletal anabolic actions of PTH (Bikle et al 2002, Yamaguchi et al 2005, Wang et al 2007, we examined the expression of PTHR and IGF1 in the mandibles and long bones by immunohistochemistry and western blots. Our results revealed that the levels of PTHR and IGF1 expressed in osteoblasts were reduced slightly in the dental alveolar bone of mandibles, but were enhanced in the trabecular bone of tibiae in the adult 1a(OH)ase K/K mice.…”

Section: Discussionmentioning

confidence: 99%

Distinctive anabolic roles of 1,25-dihydroxyvitamin D3 and parathyroid hormone in teeth and mandible versus long bones

Liu¹,

Guo²,

Wang³

et al. 2009

Journal of Endocrinology

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To assess the roles of 1,25-dihydroxyvitamin D (1,25(OH) 2 D) and parathyroid hormone (PTH) in hard tissue formation in oro-facial tissues, we examined the effect of either 1,25(OH) 2 D or PTH deficiency on dentin and dental alveolar bone formation and mineralization in the mandibles, and osteoblastic bone formation in long bones of 1a-hydroxylase knockout (1a(OH)aseCompared with wild-type mice, the mineral density was decreased in the teeth and mandibles, and unmineralized dentin (predentin and biglycan immunopositive dentin) and unmineralized bone matrix in the dental alveolar bone were increased in 1a(OH)ase K/K mice. The dental volume, reparative dentin volume, and dentin sialoprotein immunopositive areas were reduced in 1a(OH)ase K/K mice. The cortical thickness, dental alveolar bone volume, and osteoblast number were all decreased significantly in the mandibles; in contrast, the osteoblast number and surface were increased in the trabecular bone of the tibiae in 1a(OH)ase K/K mice consistent with their secondary hyperparathyroidism. The expression of PTH receptor and IGF1 was reduced slightly in mandibles, but enhanced significantly in the long bones in the 1a(OH)ase K/K mice. To control for the role of secondary hyperparathyroidism, we also examined teeth and mandibles in 6-week-old PTH K/K mice. In these animals, dental and bone volumes in mandibles were not altered when compared with their wild-type littermates. These results suggest that 1,25(OH) 2 D 3 plays an anabolic role in both dentin and dental alveolar bone as it does in long bones, whereas PTH acts predominantly in long bones rather than mandibular bone.

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Section: Discussionmentioning

confidence: 99%

Distinctive anabolic roles of 1,25-dihydroxyvitamin D3 and parathyroid hormone in teeth and mandible versus long bones

Liu¹,

Guo²,

Wang³

et al. 2009

Journal of Endocrinology

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“…Deleting IGF-IR at the stage of osteoprogenitor development by Cre-lox recombination using an osterix promoter-driven Cre mouse line, results in delayed osteoblast maturation, matrix synthesis and mineralization, without affecting the differentiation or function of osteoclasts (57). When IGF-IR is deleted in mature osteoblasts, using OCN promoter-driven Cre line, the KO mice produce less trabecular bone, with an increased proportion of osteoid in the bone, indicating impaired mineralizing functions in OCN IGF-IR -/-osteoblasts (58)(59). In contrast, overexpressing IGF-I in mature osteoblasts increases bone formation, with a significant decrease in the mineralization lag time (the time for osteoid to be mineralized), but without a change in osteoblast number (60).…”

Section: Igf-i Signaling In the Osteoblastic Lineagementioning

confidence: 99%

“…Intermittent PTH fails to elicit skeletal anabolism in global IGF-I KO mice (51,(82)(83), or in mice lacking the expression of IRS-1 (84). Similarly, ablation of IGF-IR in mature osteoblasts prevents the anabolic effects of intermittent PTH in OCN IGF-IR -/-mice (59). Interestingly, ablating IGF-I in the liver does not affect PTH-induced anabolism in bone (85).…”

Section: Integration Of Local Igf-i/igf-ir Signaling With Systemic Homentioning

confidence: 99%

Autocrine and Paracrine Actions of IGF-I Signaling in Skeletal Development

2013

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“…A number of microarray studies of PTH-treated whole bone or osteoblasts have identified thousands of genes regulated by PTH. (21)(22)(23) Many of these genes have been identified to play a role in PTH anabolic action in studies of knockout mice, including transcription factors ATF4 (18) and CREM (24) ; signaling molecules such as b-arrestin (25) ; cytokines such as fibroblast growth factor 2 (FGF2), (16) interleukin 18 (IL-18), (15) and insulin-like growth factor 1 (IGF-1) (26) ; matrix proteins including osteonectin (27) ; and other factors that regulate Wnt pathway signaling including secreted Frizzled-related protein 1 (sFRP-1). (28,29) Surprisingly, given the results in SOST transgenic mice, anabolic treatment with PTH was just as effective in the absence of low density lipoprotein receptorrelated protein 5 (LRP5) as in wild-type mice.…”

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confidence: 99%

Building bone with a SOST-PTH partnership

Sims

2010

Journal of Bone and Mineral Research

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T he discovery of the SOST gene, whose protein product, sclerostin, is an osteocyte-derived inhibitor of Wnt signalling and bone formation, (1,2) has provided a major advance in bone biology. It gives us new insights into the communicating networks among bone cells and, importantly, to new ways of restoring bone once it has been lost. In the current issue of JBMR, Kramer and colleagues complement their earlier demonstration that parathyroid hormone (PTH) inhibits sclerostin expression (3) to show that the anabolic effect of PTH is blunted both in mice overexpressing sclerostin and in SOST null mice. (4) PTH administered by daily injection is the only currently available anabolic therapy for bone. (5,6) While a number of contributing pathways, including direct prodifferentiation (7) and antiapoptotic (8) actions on osteoblasts, as well as couplingrelated activity through the osteoclast, (9) have been proposed, the full mechanism of action of anabolic PTH remains obscure. Another contributory mechanism was introduced by the discovery of sclerostin and its regulation by both PTH and PTH-related protein (PTHrP) via a distal enhancer of the SOST gene. (3,10) The experiments reported by Kramer and colleagues (4) provide further evidence that sclerostin regulation may play a part in PTH anabolic action. Mice overexpressing sclerostin have less bone as a result of decreased bone-formation rate, as described previously. (11) When these mice were treated with a high dose of PTH, sufficient to increase trabecular bone volume (BV/TV) in wild-type mice, no increase in trabecular bone volume was detected despite a robust reduction in sclerostin expression. It is worth noting that even though sclerostin mRNA levels are reduced by PTH in the transgenic model, total sclerostin expression after PTH treatment is still greater than in wild-type mice. This high level of sclerostin expression, the basal phenotype of a mild reduction in bone remodeling, or both impair the effect of PTH on BV/TV. Surprisingly, even though BV/ TV was not increased, all histomorphometric markers of bone formation, as well as the osteoclast surface, were substantially elevated by PTH treatment in the sclerostin transgenic mice to approximately the same extent as that observed in wild-type mice. Thus a question in the sclerostin transgenic model remains as to how PTH can increase bone turnover without altering BV/ TV. Is osteoclast function enhanced? No evidence was obtained for that. An alternative explanation could be that the sclerostin overexpressing mice lay down bone of reduced quality that is easier for osteoclasts to resorb. The quality of bone in the sclerostin overexpressing mouse is not yet known. Resolving this paradox may provide useful information about the interaction between osteoclasts and osteoblasts in the presence of high levels of sclerostin and, presumably, low levels of b-cateninactivated gene transcription.In SOST null mice, as expected from the skeletal abnormalities observed in van Buchem disease and sclerosteosis, (12) trabecular...

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IGF-I Receptor Is Required for the Anabolic Actions of Parathyroid Hormone on Bone

Cited by 135 publications

References 43 publications

Distinctive anabolic roles of 1,25-dihydroxyvitamin D3 and parathyroid hormone in teeth and mandible versus long bones

Distinctive anabolic roles of 1,25-dihydroxyvitamin D3 and parathyroid hormone in teeth and mandible versus long bones

Autocrine and Paracrine Actions of IGF-I Signaling in Skeletal Development

Building bone with a SOST-PTH partnership

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