Parathyroid hormone increases the concentration of insulin-like growth factor-I and transforming growth factor beta 1 in rat bone.

Combined IGF-I and TGF-β1 application by a poly-(D,Llactide) (PDLLA) coated interbody cage has proven to promote spine fusion. The purpose of this study was to determine whether there is a dosedependent effect of combined IGF-I and TGF-β1 application on intervertebral bone matrix formation in a sheep cervical spine fusion model. Thirty-two sheep underwent C3/4 discectomy and fusion. Stabilisation was performed using a titanium cage coated with a PDLLA carrier including no growth factors in group 1 (n=8), 75 µg IGF-I plus 15 µg TGF-β1 in group 2 (n=8), 150 µg IGF-I plus 30 µg TGF-β1 in group 3 (n=8) and 300 µg IGF-I plus 60 µg TGF-β1 in group 4 (n=8). Blood samples, body weight and temperature were analysed. Radiographic scans were performed pre-and postoperatively and after 1, 2, 4, 8, and 12 weeks. At the same time points, disc space height and intervertebral angle were measured. After 12 weeks, the animals were killed and fusion sites were evaluated using quantitative computed tomographic (CT) scans to assess bone mineral density, bone mineral content and bony callus volume. Biomechanical testing was performed and range of motion, and

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“…They concluded that both growth factors had synergistic effects on fracture healing. Similar conclusions were drawn by other authors [33,43].…”

Section: Fluorochrome Analysis Resultssupporting

confidence: 93%

Dose-dependent effects of combined IGF-I and TGF-β1 application in a sheep cervical spine fusion model

et al. 2002

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“…The images were stored in three-dimensional arrays with an isotropic voxel size of either 34 m (for the whole bone) or 9 m (for the distal femoral metaphysis). Morphometric parameters were computed using a direct three-dimensional approach that does not rely on any assumptions about whether the underlying structure is either plate or rod-like (25). For the whole bone, we computed the total bone volume (BV, mm 3 ) and the apparent volume density (AVD, %), defined as the percent of mineralized tissue volume divided by the total volume defined by the external bone envelope (24).…”

Section: Methodsmentioning

confidence: 99%

Osteoblast-specific Knockout of the Insulin-like Growth Factor (IGF) Receptor Gene Reveals an Essential Role of IGF Signaling in Bone Matrix Mineralization

Zhang

Xuan

Bouxsein

et al. 2002

Journal of Biological Chemistry

641

561

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To examine the local actions of IGF signaling in skeletal tissue in a physiological context, we have used Cremediated recombination to disrupt selectively in mouse osteoblasts the gene encoding the type 1 IGF receptor (Igf1r). Mice carrying this bone-specific mutation were of normal size and weight but, in comparison with normal siblings, demonstrated a striking decrease in cancellous bone volume, connectivity, and trabecular number, and an increase in trabecular spacing. These abnormalities correlated with a striking decrease in the rate of mineralization of osteoid that occurred despite an unexpected osteoblast and osteoclast hyperactivity, detected from the significant increments in both osteoblast and erosion surfaces. Our findings indicate that IGF1 is essential for coupling matrix biosynthesis to sustained mineralization. This action is likely to be particularly important during the pubertal growth spurt when rapid bone formation and consolidation are required.Body size and linear bone growth in mammals is affected by cellular signaling pathways controlled by growth factors and hormones (1). In this regard, a major growth-promoting signaling system consisting of the insulin-like growth factors (IGF, 1 IGF1 and IGF2) and the type 1 IGF receptor (IGF1R) regulates embryonic growth, as shown by gene knockout experiments in mice (1). IGF1 acting through IGF1R also plays central roles in postnatal growth either independently or by mediating growth hormone functions (2). Signaling through the IGF1R tyrosine kinase receptor not only promotes cell proliferation, but also mediates anti-apoptotic actions (3, 4). The IGF system includes a second receptor (IGF2R) devoid of signaling properties, but serving IGF2 turnover, and at least six IGF-binding proteins (IGFBPs) of obscure functional significance (single and also some double mouse mutations ablating IGFBPs have not revealed as yet significant consequences in growth impairment). 2 The IGFs are produced locally in various tissues, including bones, and exert autocrine/paracrine functions, but they are also present in serum, mostly associated with IGFBPs. Whether the circulating IGFs act systemically as hormones is currently controversial (5, 6).A number of in vitro and in vivo studies are progressively unraveling the significance of the IGF system for skeletal development and metabolic control (for a review see Ref. 7). IGF1, by stimulating the proliferation of chondrocytes in the growth plate, plays an essential role in longitudinal bone growth (2) and is also involved in the formation of trabecular bone. In fact, chondrocytes and bone cells produce IGFs and express IGF1R (see for example Refs. 8 and 9). Studies using osteoblast culture systems have shown that IGF1 stimulates osteoblast proliferation, accelerates their differentiation, and enhances bone matrix production (10, 11). In addition, IGF1 is being recognized as a critical factor for bone cell survival (12)(13)(14). Finally, IGF1 also appears to regulate bone resorption, either directly or through its actio...

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“…As in human cells, in vitro PTH stimulation increases of production of TGFb1 and IGF-1 by murine osteoblasts (Cho et al, 2013, McCarthy et al, 1989, Pfeilschifter et al, 1995. However, the effects of iPTH treatment on the production of these factors is largely unknown.…”

Section: Ipth Treatment In Mice Expands the Pool Of Murine Bm Tregs Bmentioning

confidence: 99%

“…Recently, IGF-1 has been recognized as an additional inducer of Tregs (Anguela, Tafuro et al, 2013, Johannesson, Sattler et al, 2014. Since iPTH increases TGFb and IGF-1 production in bone (Cho, Pirih et al, 2013, McCarthy, Centrella et al, 1989, Pfeilschifter, Laukhuf et al, 1995, it is likely that iPTH may induce and/or expand BM Tregs.…”

Section: Introductionmentioning

confidence: 99%

Regulatory T cells are expanded by Teriparatide treatment in humans and mediate intermittent PTH ‐induced bone anabolism in mice

D’Amelio

Tyagi

et al. 2017

EMBO Reports

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Teriparatide is a bone anabolic treatment for osteoporosis, modeled in animals by intermittent PTH (iPTH) administration. iPTH-induced bone anabolism involves CD8+ T cell production of the osteogenic Wnt ligand Wnt10b, induced via yet unknown mechanisms. Here we show that Teriparatide and iPTH cause a ~2-3-fold increase in the number of regulatory T cells (Tregs) in humans and mice. Attesting in vivo relevance, blockade of the Treg increase in mice prevents iPTH-induced CD8+ T cell Wnt10b production and bone anabolism. Mechanistically, Treg action on CD8+ T cells promotes binding of NFAT1/2 and SMAD3 complexes to a NFAT/SMADactivated Wnt10b promoter region that stimualtes Wnt10b gene expression in CD8+ T cells.

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Parathyroid hormone increases the concentration of insulin-like growth factor-I and transforming growth factor beta 1 in rat bone.

Cited by 146 publications

References 37 publications

Dose-dependent effects of combined IGF-I and TGF-β1 application in a sheep cervical spine fusion model

Dose-dependent effects of combined IGF-I and TGF-β1 application in a sheep cervical spine fusion model

Osteoblast-specific Knockout of the Insulin-like Growth Factor (IGF) Receptor Gene Reveals an Essential Role of IGF Signaling in Bone Matrix Mineralization

Regulatory T cells are expanded by Teriparatide treatment in humans and mediate intermittent PTH ‐induced bone anabolism in mice

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