Parathyroid hormone exerts disparate effects on osteoblast differentiation depending on exposure time in rat osteoblastic cells.

Ishizuya, Toshinori; Yokose, Satoshi; Hori, Masayuki; Noda, Toshiharu; Suda, Toshio; Yoshiki, Shusaku; Yamaguchi, Akira

doi:10.1172/jci119491

Cited by 328 publications

(253 citation statements)

References 47 publications

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“…Error bars represent S.E. tured cells under osteogenic conditions with PTH or PBS for 6 h of every 48 h to stimulate osteoblast differentiation (53). In control osteoblasts, PTH increased mineralized nodule formation after 14 days, and as reported previously, deletion of G s ␣ led to markedly enhanced mineralization (35).…”

Section: Resultssupporting

confidence: 58%

Loss of Gsα in the Postnatal Skeleton Leads to Low Bone Mass and a Blunted Response to Anabolic Parathyroid Hormone Therapy

Sinha

Aarnisalo

Chubb

et al. 2016

Journal of Biological Chemistry

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. Surprisingly, in both male and female mice, PTH administration significantly increased osteoblast numbers and bone formation rate in both control and P-G s ␣ OsxKO mice. In mice that express a mutated PTH1R that activates adenylyl cyclase and protein kinase A (PKA) via G s ␣ but not phospholipase C via G q/11 (D/D mice), PTH significantly enhanced bone formation, indicating that phospholipase C activation is not required for increased bone turnover in response to PTH. Therefore, although the anabolic effect of intermittent PTH treatment on trabecular bone volume is blunted by deletion of G s ␣ in osteoblasts, PTH can stimulate osteoblast differentiation and bone formation. Together these findings suggest that alternative signaling pathways beyond G s ␣ and G q/11 act downstream of PTH on osteoblast differentiation.

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Section: Resultssupporting

confidence: 58%

Loss of Gsα in the Postnatal Skeleton Leads to Low Bone Mass and a Blunted Response to Anabolic Parathyroid Hormone Therapy

Sinha

Aarnisalo

Chubb

et al. 2016

Journal of Biological Chemistry

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“…In contrast to the in vivo and in vitro evidence for a direct anti-mitotic action of short term exposure of osteoblast progenitors to PTH, osteogenic cell replication was stimulated by 6 hours of exposure to PTH or PTHrP in cultures established from the bone marrow [69] or calvaria [70] of young rats. In addition, treatment of embryonic chick periosteal cells with PTH for 5-30 minutes stimulated proliferation [71].…”

Section: Effects Of Intermittent Pth On the Replication And Differentmentioning

confidence: 59%

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

Jilka

2007

Bone

631

531

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Intermittent administration of parathyroid hormone (PTH) stimulates bone formation by increasing osteoblast number, but the molecular and cellular mechanisms underlying this effect are not completely understood. In vitro and in vivo studies have shown that PTH directly activates survival signaling in osteoblasts; and that delay of osteoblast apoptosis is a major contributor to the increased osteoblast number, at least in mice. This effect requires Runx2-dependent expression of antiapoptotic genes like Bcl-2. PTH also causes exit of replicating progenitors from the cell cycle by decreasing expression of cyclin D and increasing expression of several cyclin-dependent kinase inhibitors. Exit from the cell cycle may set the stage for pro-differentiating and pro-survival effects of locally produced growth factors and cytokines, the level and/or activity of which are known to be influenced by PTH. Observations from genetically modified mice suggest that the anabolic effect of intermittent PTH requires insulin-like growth factor-I (IGF-I), fibroblast growth factor-2 (FGF-2), and perhaps Wnts. Attenuation of the negative effects of PPARγ may also lead to increased osteoblast number. Daily injections of PTH may add to the pro-differentiating and pro-survival effects of locally produced PTH related protein (PTHrP). As a result, osteoblast number increases beyond that needed to replace the bone removed by osteoclasts during bone remodeling. The pleiotropic effects of intermittent PTH, each of which alone may increase osteoblast number, may explain why this therapy reverses bone loss in most osteoporotic individuals regardless of the underlying pathophysiology.

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“…Some studies have found that PTH exerts anti-apoptotic actions in osteoblasts through PKA signaling (35,36). Others have reported that intermittent treatment with PTH stimulates bone anabolism through both PKA and PKC pathways in osteoblasts (37). However, it has been reported that PKC activity inhibits osteoblast differentiation (38).…”

Section: Discussionmentioning

confidence: 99%

Parathyroid Hormone-responsive Smad3-related Factor, Tmem119, Promotes Osteoblast Differentiation and Interacts with the Bone Morphogenetic Protein-Runx2 Pathway

Hisa

Inoue

Hendy

et al. 2011

Journal of Biological Chemistry

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The mechanisms whereby the parathyroid hormone (PTH) exerts its anabolic action on bone are incompletely understood. We previously showed that inhibition of ERK1/2 enhanced Smad3-induced bone anabolic action in osteoblasts. These findings suggested the hypothesis that changes in gene expression associated with the altered Smad3-induced signaling brought about by an ERK1/2 inhibitor would identify novel bone anabolic factors in osteoblasts. We therefore performed a comparative DNA microarray analysis between empty vector-transfected mouse osteoblastic MC3T3-E1 cells and PD98059-treated stable Smad3-overexpressing MC3T3-E1 cells. Among the novel factors, Tmem119 was selected on the basis of its rapid induction by PTH independent of later increases in endogenous TGF-␤. The levels of Tmem119 increased with time in cultures of MC3T3-E1 cells and mouse mesenchymal ST-2 cells committed to the osteoblast lineage by BMP-2. PTH stimulated Tmem119 levels within 1 h as determined by Western blot analysis and immunocytochemistry in MC3T3-E1 cells. MC3T3-E1 cells stably overexpressing Tmem119 exhibited elevated levels of Runx2, osteocalcin, alkaline phosphatase, and ␤-catenin, whereas Tmem119 augmented BMP-2-induced Runx2 levels in mesenchymal cells. Tmem119 interacted with Runx2, Smad1, and Smad5 in C2C12 cells. In conclusion, we identified a Smad3-related factor, Tmem119, that is induced by PTH and promotes differentiation in mouse osteoblastic cells. Tmem119 is an important molecule in the pathway downstream of PTH and Smad3 signaling in osteoblasts.Bone remodeling is controlled by bone resorption and subsequent osteoblastic bone formation. Insights into the mechanisms of osteoclastic bone resorption have led to the development of reagents that potently suppress bone resorption for the treatment of osteoporosis. On the other hand, the impairment of osteoblastic bone formation is considered to be the main driving force in age-related, glucocorticoid-induced, and diabetes-related osteoporosis. However, many aspects of osteoblastic bone formation remain to be understood. Intermittent parathyroid hormone (PTH) 3 is one of the most potent anabolic agents; it stimulates de novo osteoblastic bone formation and is superior to bisphosphonates in the treatment of osteoporosis (1, 2). The anabolic action of PTH is exerted partly through local growth factors and transcriptional regulators as well by as an anti-apoptotic action in osteoblasts (3, 4). However, the precise mechanisms by which PTH exerts its anabolic action on bone are incompletely understood.We showed previously that Smad3, a crucial TGF-␤-signaling molecule, promotes alkaline phosphatase (ALP) activity in mouse osteoblastic MC3T3-E1 cells (5, 6), and Borton et al. (7) have found that mice with targeted disruption of Smad3 exhibit osteopenia caused by decreased bone formation, suggesting that the Smad3 molecule is a promoter of bone formation. Moreover, we demonstrated that TGF-␤-responsive ERK1/2 and c-Jun N-terminal kinase (JNK) cascades negatively regulate Smad3-ind...

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Parathyroid hormone exerts disparate effects on osteoblast differentiation depending on exposure time in rat osteoblastic cells.

Cited by 328 publications

References 47 publications

Loss of Gsα in the Postnatal Skeleton Leads to Low Bone Mass and a Blunted Response to Anabolic Parathyroid Hormone Therapy

Loss of Gsα in the Postnatal Skeleton Leads to Low Bone Mass and a Blunted Response to Anabolic Parathyroid Hormone Therapy

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

Parathyroid Hormone-responsive Smad3-related Factor, Tmem119, Promotes Osteoblast Differentiation and Interacts with the Bone Morphogenetic Protein-Runx2 Pathway

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