Parathyroid hormone restores bone mass and enhances osteoblast insulin-like growth factor I gene expression in ovariectomized rats

Watson, Patricia H.; Lazowski, D.-A.; Han, V. K. M.; Fraher, L. J.; Steer, Brent M.; Hodsman, Anthony B.

doi:10.1016/8756-3282(94)00051-4

Cited by 162 publications

(90 citation statements)

References 38 publications

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“…In rats, 4 weeks of daily PTH injections increased IGF-I transcripts in osteoblasts as determined by in situ hybridization [85]. Interestingly, however, mRNA levels were not affected by short term exposure of cultured osteoblastic cells to PTH [86].…”

Section: Igf-imentioning

confidence: 92%

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

Jilka

2007

Bone

623

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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Section: Igf-imentioning

confidence: 92%

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

Jilka

2007

Bone

623

531

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“…PTH modifies the bone marrow microenvironment by orchestrating the signaling of local factors for bone remodeling, reducing ROS, and stimulating Wnt signaling in the bones of old mice (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). PTH is an FDA-approved anabolic therapy for osteoporosis, and daily injection of PTH increases bone formation with normal microarchitecture by coupling bone remodeling (7)(8)(9)(10)(11)(12)(13)(14)(15). PTH treatment has been shown to attenuate osteoarthritis progression in animal models (116,117).…”

Section: Potential Treatment Of Uncoupled Bone Remodeling Disordersmentioning

confidence: 99%

“…Thus, the fate of MSCs and other cells in the microenvironment are indirectly regulated by PTH to integrate systemic control of bone remodeling (Figure 1 and refs. [7][8][9][10][11][12][13][14][15].…”

Section: Pth Modulates the Bone Marrow Microenvironmentmentioning

confidence: 99%

“…During osteoclastmediated bone resorption, multiple factors are released from the bone matrix and/or secreted locally, creating an osteogenic microenvironment that promotes MSC recruitment and osteoblast differentiation for new bone formation (3)(4)(5)(6). Parathyroid hormone (PTH), the systemic hormone that regulates calcium homeostasis, plays a major role in orchestrating bone remodeling by modulating the bone marrow microenvironment and regulating osteogenic signaling pathways (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Latent TGF-β1, which is abundant in the bone matrix, is released and activated by osteoclasts to specifically induce migration of MSCs to bone-resorptive sites (17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

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Bone marrow mesenchymal stem cells and TGF-β signaling in bone remodeling

Crane¹,

Cao²

2014

J. Clin. Invest.

376

300

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During bone resorption, abundant factors previously buried in the bone matrix are released into the bone marrow microenvironment, which results in recruitment and differentiation of bone marrow mesenchymal stem cells (MSCs) for subsequent bone formation, temporally and spatially coupling bone remodeling. Parathyroid hormone (PTH) orchestrates the signaling of many pathways that direct MSC fate. The spatiotemporal release and activation of matrix TGF-β during osteoclast bone resorption recruits MSCs to bone-resorptive sites. Dysregulation of TGF-β alters MSC fate, uncoupling bone remodeling and causing skeletal disorders. Modulation of TGF-β or PTH signaling may reestablish coupled bone remodeling and be a potential therapy. IntroductionIn humans, the skeleton undergoes continuous remodeling throughout adulthood. To maintain skeletal integrity, the activity of two cell types must be precisely coordinated. Osteoclasts, which resorb bone, are multinucleated cells derived from macrophages/monocytes in the HSC lineage. Osteoblasts, which deposit calcified bone matrix, are derived from bone marrow mesenchymal stem cells (MSCs; also referred to as bone marrow stromal cells or skeletal stem cells; ref. 1). The bone remodeling cycle is characterized by three distinct phases: (a) initiation, during which osteoclasts are formed and resorb damaged bone; (b) reversal, the transition of osteoclast to osteoblast activity; and (c) formation, when osteoblasts replace the portion of bone that was resorbed (2). Key steps in the reversal period include termination of osteoclast bone resorption and recruitment/differentiation of MSCs (2). Skeletal homeostasis is maintained by precise regulatory mechanisms during the reversal phase.The bone marrow microenvironment that is created during osteoclast bone resorption directs MSC fate. During osteoclastmediated bone resorption, multiple factors are released from the bone matrix and/or secreted locally, creating an osteogenic microenvironment that promotes MSC recruitment and osteoblast differentiation for new bone formation (3-6). Parathyroid hormone (PTH), the systemic hormone that regulates calcium homeostasis, plays a major role in orchestrating bone remodeling by modulating the bone marrow microenvironment and regulating osteogenic signaling pathways (7-16). Latent TGF-β1, which is abundant in the bone matrix, is released and activated by osteoclasts to specifically induce migration of MSCs to bone-resorptive sites (17)(18)(19). Because these two pathways have specific effects on MSC fate, their coordinated regulation is critical to bone remodeling.Here, we discuss the current understanding of how the bone marrow microenvironment at resorption sites affects MSCs and contributes to coupled bone remodeling. We specifically focus on how PTH regulates the osteogenic bone marrow microenvironment and how TGF-β promotes MSC recruitment. We also describe specific skeletal diseases that result from disruption of coupled bone remodeling. Finally, we address how modulation of TGF-β or PTH signal...

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“…2 Anabolic functions are stimulated by intermittent exposure to PTH, resulting in differentiation and proliferation or reduced apoptosis of osteoblasts. [3][4][5] Catabolic functions are stimulated by continuous PTH exposure and associated with increased receptor activator of nuclear factor-κB ligand expression and inhibition of osteoprotegerin expression.…”

Section: Introductionmentioning

confidence: 99%

Preparation and in vivo evaluation of an orally available enteric-microencapsulated parathyroid hormone (1-34)-deoxycholic acid nanocomplex

Hwang¹,

Seo²,

Byun³

et al. 2016

IJN

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The N -terminal 34-amino-acid peptide fragment of human parathyroid hormone PTH (1-34), is used clinically to treat osteoporosis; however, it is currently administered by a once-daily subcutaneous injection, resulting in poor patient compliance. We have developed enteric microcapsules containing an ionic nanocomplex between PTH (1-34) and lysine-linked deoxycholic acid (LysDOCA) for the oral delivery of PTH (1-34). We measured the particle size of the PTH/LysDOCA complex and assessed its biological activity by determining the cAMP content in MC3T3-E1 cells. We also assessed its permeability across a Caco-2 cell monolayer and the bioavailability of the intrajejunally administered PTH/LysDOCA complex compared with PTH (1-34) in rats. In addition, the antiosteoporotic activity of the PTH/LysDOCA complex, encapsulated in an enteric carrier by coaxial ultrasonic atomization, was evaluated after it was orally administered to ovariectomized (OVX) rats. The formation of an ionic complex between PTH (1-34) and LysDOCA produced nanoparticles of diameter 33.0±3.36 nm, and the bioactivity of the complex was comparable with that of PTH (1-34). The Caco-2 cell permeability and AUC last value of the PTH/LysDOCA (1:10) nanocomplex increased by 2.87- and 16.3-fold, respectively, compared with PTH (1-34) alone. Furthermore, the OVX rats treated with oral PTH/LysDOCA-loaded enteric microcapsules showed an increase in bone mineral density (159%), bone volume fraction (175%), and trabecular number (174%) compared with those in the OVX control group. Therefore, the PTH/LysDOCA nanocomplex oral delivery system is a promising treatment modality for osteoporosis because it improves osteogenesis and trabecular connectivity.

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Parathyroid hormone restores bone mass and enhances osteoblast insulin-like growth factor I gene expression in ovariectomized rats

Cited by 162 publications

References 38 publications

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

Bone marrow mesenchymal stem cells and TGF-β signaling in bone remodeling

Preparation and in vivo evaluation of an orally available enteric-microencapsulated parathyroid hormone (1-34)-deoxycholic acid nanocomplex

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