Bone Mass Loss Due to Estrogen Deficiency Is Compensated in Transgenic Mice Overexpressing Human Osteoblast Stimulating Factor-1

Masuda, Haruchika; Tsujimura, Akira; Yoshioka, Makoto; Arai, Yuji; Kuboki, Yoshinori; Mukai, Tsunehiro; Nakamura, Toshio; Tsuji, Hajime; Nakagawa, Masao; Hashimoto-Gotoh, Tamotsu

doi:10.1006/bbrc.1997.7188

Cited by 45 publications

(30 citation statements)

References 22 publications

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“…In fact, the three transgenic mouse models overexpressing Ptn all display a higher bone mineral density, which is in line with in vitro experiments demonstrating that Ptn promotes migration, differentiation, and function of osteoblasts. (21)(22)(23)(44)(45)(46) In addition, there is recent evidence that these effects are also of physiologic relevance because low bone formation and osteopenia have been described in mice lacking Ptn. (47) Given the fact that our own analysis of Ptn-deficient mice did not reveal such a phenotype compared with wild-type littermates on a mixed genetic background, it appears that the backcrossing of the Ptn deficiency into a 129S2/SV genetic background is primarily responsible for the discrepancies between the two publications.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, there are three published transgenic mouse models overexpressing Ptn, all of them displaying a bone phenotype. (21)(22)(23) Together with the fact that Ptn was identified originally not only in the developing brain but also in cultured osteoblasts, and given the positive effect of Ptn on osteoblast proliferation and differentiation in vitro, we embarked previously on the skeletal analysis of a Ptn-deficient mouse model to address the question of whether Ptn is physiologically involved in the regulation of bone remodeling. (24)(25)(26)(27) Unexpectedly, however, our analysis did not reveal any defect of skeletal development and remodeling caused by the absence of Ptn.…”

Section: Introductionmentioning

confidence: 99%

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Increased trabecular bone formation in mice lacking the growth factor midkine

Neunaber

Catalá-Lehnen

Beil

et al. 2010

Journal of Bone and Mineral Research

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Midkine (Mdk) and pleiotrophin (Ptn) comprise a family of heparin-binding growth factors known primarily for their effects on neuronal cells. Since transgenic mice overexpressing Ptn have been reported to display increased bone density, we have previously analyzed Ptndeficient mice but failed to detect any abnormality of skeletal development and remodeling. Together with the finding that Mdk expression increases in the course of primary osteoblast differentiation, we reasoned that Mdk, rather than Ptn, could play a physiologic role in bone formation. Here, we show that Mdk-deficient mice display an increased trabecular bone volume at 12 and 18 months of age, accompanied by cortical porosity. Histomorphometric quantification demonstrated an increased bone-formation rate compared with wild-type littermates, whereas bone resorption was differentially affected in trabecular and cortical bone of Mdk-deficient mice. To understand the effect of Mdk on bone formation at the molecular level, we performed a genome-wide expression analysis of primary osteoblasts and identified Ank and Enpp1 as Mdk-induced genes whose decreased expression in Mdk-deficient osteoblasts may explain, at least in part, the observed skeletal phenotype. Finally, we performed ovariectomy and observed bone loss only in wild-type but not in Mdk-deficient animals. Taken together, our data demonstrate that Mdk deficiency, at least in mice, results in an increased trabecular bone formation, thereby raising the possibility that Mdk-specific antagonists might prove beneficial in osteoporosis therapy. ß

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Increased trabecular bone formation in mice lacking the growth factor midkine

Neunaber

Catalá-Lehnen

Beil

et al. 2010

Journal of Bone and Mineral Research

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“…Flt-1 and KDR also act as receptors for other members of the VEGF family (Clark and Charnock-Jones, 1999). Of particular interest is the fact that the VEGF-165 splice variant has been found to bind the neurophilin-1 receptor in osteogenic cells (Harper et al, 2001).Pleiotrophin is also known as heparin-binding growthassociated molecule (HB-GAM) (Rauvala, 1989), osteoblast-stimulating factor-1 (OSF-1) (Masuda et al, 1997), and heparin affinity regulatory peptide (HARP) (Papadimitriou et al, 2001). Receptors associated with pleiotrophin and its neurotrophic effects are N-syndecan/syndecan-3 and RPTPb/PTPf (Raulo et al, 1994;Maeda et al, 1996).…”

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confidence: 99%

“…Pleiotrophin is also known as heparin-binding growthassociated molecule (HB-GAM) (Rauvala, 1989), osteoblast-stimulating factor-1 (OSF-1) (Masuda et al, 1997), and heparin affinity regulatory peptide (HARP) (Papadimitriou et al, 2001). Receptors associated with pleiotrophin and its neurotrophic effects are N-syndecan/syndecan-3 and RPTPb/PTPf (Raulo et al, 1994;Maeda et al, 1996).…”

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confidence: 99%

Expression of VEGF and pleiotrophin in deer antler

2006

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Deer antlers represent a unique model of mammalian regeneration in that they cast and fully regenerate every year. The deer antler thus provides a fascinating model of both rapid angiogenesis and chondrogenesis and the opportunity to investigate unique growth regulatory processes. One such phenomenon is the presence of vascularized cartilage in the growing antler tip-unlike other cartilage, which is typically avascular. The mechanisms by which blood vessels grow in the cartilage as well as the factors that drive antler extension at approximately 1 cm a day have been hitherto largely unknown. The aim of this study was to determine the expression of VEGF and pleiotrophin within the growing antler tip. We isolated cervine VEGF121 and VEGF165 from deer antler and found that mRNA is produced for VEGF in the precartilage and cartilage regions. By in situ hybridization, we examined whether the VEGF receptors Flt-1 and KDR are present in deer antler and found only KDR mRNA within the endothelial cells of the precartilage region. This finding is compatible with VEGF having an angiogenic effect within antler. Pleiotrophin mRNA was found in the vascular smooth muscle cells of the dermis, thus supporting a possible role in vascular growth. High levels of pleiotrophin mRNA were also detected in the precartilage region with possible implications for both angiogenesis and chondrogenesis. This is the first report of cervine angiogenic growth factors within the growing antler tip. Anat Rec Part A, 288A: 1281-1293, 2006. 2006 Key words: angiogenesis; cartilage; chondrogenesis; endothelial Systems where growth occurs at an astonishing rate such as the placenta, embryo, and deer antler can give important insights into the mechanisms involved in angiogenesis. Deer antlers are unique mammalian appendages in that they have an annual cycle of regeneration. During regeneration, the cartilage, skin, nerves, and blood vessels of the antler must grow at a rapid rate. This full regrowth occurs under conditions of low testosterone and high plasma IGF-1 during spring (Li et al., 2003). Antler grows at varying rates in different species, with growth rates reaching 12.5 mm/day in sika deer (Gao and Li, 1988), 27.5 mm/day in moose (Goss, 1970), and approximately 10 mm/day in red deer (Fennessy et al., 1991). Antler growth is driven from the tip, which consists of dermis, mesenchyme, precartilage, and the cartilage that transforms to bone and that then progressively calcifies within the antler (Fig. 1). Antlerogenic stem cells have been found to be concentrated in the reserve mesenchyme underlying the dermis (Li et al., 2002(Li et al., , 2005a. Cells from the reserve mesenchyme divide and differentiate, thus contributing chondroblasts to the precartilage region, where progressive maturation occurs. The cartilage zone contains columns of chondrocytes and large parallel vascular channels, which give a red appearance. In the region shown as the remodeling zone (Fig. 1) THE ANATOMICAL RECORD PART A 288A: 1281-1293 (2006) expand at a rapi...

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“…BMCs and BMD of grafted bone were measured by the ash method and dual-energy X-ray absorptiometry (DEXA), respectively. 28 Bone sample was excised and soft tissue and Matrigel surrounding the bone were completely removed. BMD was determined using a DCR-600R instrument (Aloka Co., Japan) and expressed as mg/cm 2 .…”

Section: Scid Mouse Xenograft and Bone Mass Evaluationmentioning

confidence: 99%

Telomerized presenescent osteoblasts prevent bone mass loss in vivo

Yudoh

Nishioka

2004

Gene Ther

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Previously, we showed that human osteoblasts expressing the human telomerase reverse transcriptase (hTERT) gene exhibited specific survival advantages -the result of breaching the replicative senescence barrier and maintaining the phenotypic and functional properties of primary osteoblasts in vitro over the total replicative capacity of primary osteoblasts. We postulated that rejuvenated osteoblasts may have a potential to correct bone loss or osteopenia in agerelated osteoporotic diseases. In the present study, we studied whether telomerized presenescent osteoblasts prevent bone mass loss in vivo. After obtaining the informed consent from a patient with osteoarthritis who underwent the arthroplastic knee surgery, osteoblastic cells were isolated from donor bone sample. We transfected the gene encoding hTERT into human osteoblastic cells. Human bone fragments from a donor were incubated with human hTERTtransfected presenescent (in vitro aged) osteoblasts or mock-transfected presenescent osteoblasts in culture medium containing Matrigel. We subcutaneously implanted human bone fragments with telomerized presenescent osteoblasts or primary presenescent osteoblasts as threedimensional Matrigel xenografts in severe combined immunodeficiency (SCID) mice (each group: six mice) and analyzed the grafts at 6 weeks after implantation. We also determined whether telomerized osteoblasts affect the boneforming capacity in vivo, using a well-established mouse transplantation model in which ceramic hydroxyapatite/ tricalcium phosphate particles are used as carrier vehicle. Telomerized presenescent osteoblasts were rejuvenated, and maintained the functional properties of young osteoblasts in vitro. Bone mineral content (BMC) and bone mineral density (BMD) were measured by ash weight and dualenergy X-ray absorptiometry, respectively. Whereas BMC and BMD of human bone fragments, which were inoculated with aged osteoblasts in SCID mice, decreased with time, telomerized presenescent osteoblasts maintained the BMC and BMD of human bone fragments, indicating that telomerized and rejuvenated osteoblasts may be functional to prevent bone mass loss in vivo. In xenogenic transplants, telomerized osteoblasts generated more bone tissue with lamellar bone structure and cellular components, than did control osteoblasts. These findings suggest that telomerized/ rejuvenated presenescent osteoblasts may be used in the development of tissue engineering or cell-based therapy for bone regeneration and repair. Gene Therapy (2004) 11, 909-915.

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Bone Mass Loss Due to Estrogen Deficiency Is Compensated in Transgenic Mice Overexpressing Human Osteoblast Stimulating Factor-1

Cited by 45 publications

References 22 publications

Increased trabecular bone formation in mice lacking the growth factor midkine

Increased trabecular bone formation in mice lacking the growth factor midkine

Expression of VEGF and pleiotrophin in deer antler

Telomerized presenescent osteoblasts prevent bone mass loss in vivo

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