The 3.6 kb DNA fragment from the rat Col1a1 gene promoter drives the expression of genes in both osteoblast and osteoclast lineage cells

Boban, Ivana; Jacquin, Claire; Prior, Katie; Barisic-Dujmovic, Tatjana; Maye, Peter; Clark, Stephen H.; Aguila, Héctor L.

doi:10.1016/j.bone.2006.06.025

Cited by 52 publications

(72 citation statements)

References 34 publications

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“…We surmise that the reported osteoporotic phenotype of Col3.6-Cre:Rosa-Nicd Tg/Tg may be caused by early and constant Nicd activation that likely interrupts physiological lineage transition from the preosteoblast into mature osteoblasts and osteocytes (15). In addition, Col3.6-GFP has been reported to be expressed in osteoclasts (50), making it further difficult to interpret outcomes. In contrast, we report that Col3.2-CreERT:Rosa-Nicd Tg/Tg mice that are induced to overexpress Nicd in osteoblast lineage cells during adulthood display a dramatic anabolic bone phenotype.…”

Section: Discussionmentioning

confidence: 91%

Anabolic actions of Notch on mature bone

Liu

Ping

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Notch controls skeletogenesis, but its role in the remodeling of adult bone remains conflicting. In mature mice, the skeleton can become osteopenic or osteosclerotic depending on the time point at which Notch is activated or inactivated. Using adult EGFP reporter mice, we find that Notch expression is localized to osteocytes embedded within bone matrix. Conditional activation of Notch signaling in osteocytes triggers profound bone formation, mainly due to increased mineralization, which rescues both age-associated and ovariectomy-induced bone loss and promotes bone healing following osteotomy. In parallel, mice rendered haploinsufficient in γ-secretase presenilin-1 (Psen1), which inhibits downstream Notch activation, display almost-absent terminal osteoblast differentiation. Consistent with this finding, pharmacologic or genetic disruption of Notch or its ligand Jagged1 inhibits mineralization. We suggest that stimulation of Notch signaling in osteocytes initiates a profound, therapeutically relevant, anabolic response.

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Section: Discussionmentioning

confidence: 91%

Anabolic actions of Notch on mature bone

Liu

Ping

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The goal of this study was to use skeletally targeted overexpression of AR as a means of elucidating the specific role(s) for AR transactivation in the mature differentiated osteoblast. AR overexpression was targeted by the col2.3 promoterand was chosen for several reasons: the skeletal expression patterns for this promoter are bone-selective and well-characterized (see [24][25][26]36,37]); with strong col2.3 promoter activity in differentiated osteoblasts/ osteocytes and mineralizing nodules [25,26,36] but not in osteoclasts [7]. Promoter activity varies in different bone compartments.…”

Section: Introductionmentioning

confidence: 99%

Targeting of androgen receptor in bone reveals a lack of androgen anabolic action and inhibition of osteogenesis

Wiren

Semirale

Zhang

et al. 2008

Bone

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Androgens are anabolic hormones that affect many tissues, including bone. However, an anabolic effect of androgen treatment on bone in eugonadal subjects has not been observed and clinical trials have been disappointing. The androgen receptor (AR) mediates biological responses to androgens. In bone tissue, both AR and the estrogen receptor (ER) are expressed. Since androgens can be converted into estrogen, the specific role of the AR in maintenance of skeletal homoeostasis remains controversial. The goal of this study was to use skeletally targeted overexpression of AR in differentiated osteoblasts as a means of elucidating the specific role(s) for AR transactivation in the mature bone compartment. Transgenic mice overexpressing AR under the control of the 2.3-kb α1 (I)-collagen promoter fragment showed no difference in body composition, testosterone, or 17β-estradiol levels. However, transgenic males have reduced serum osteocalcin, CTx and TRAPC5b levels, and a bone phenotype was observed. In cortical bone, high-resolution micro-computed tomography revealed no difference in periosteal perimeter but a significant reduction in cortical bone area due to an enlarged marrow cavity. Endocortical bone formation rate was also significantly inhibited. Biomechanical analyses showed decreased whole bone strength and quality, with significant reductions in all parameters tested. Trabecular morphology was altered, with increased bone volume comprised of more trabeculae that were closer together but not thicker. Expression of genes involved in bone formation and bone resorption was significantly reduced. The consequences of androgen action are compartment-specific; anabolic effects are exhibited exclusively at periosteal surfaces, but in mature osteoblasts androgens inhibited osteogenesis with detrimental effects on matrix quality, bone fragility and whole bone strength. Thus, the present data demonstrate that enhanced androgen signaling targeted to bone results in low bone turnover and inhibition of bone formation by differentiated osteoblasts. These results indicate that direct androgen action in mature osteoblasts is not anabolic, and raise concerns regarding anabolic steroid abuse in the developing skeleton or high-dose treatment in eugonadal adults.

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“…The first point in support of the alternate hypothesis that at least a substantial subset of the GFP-positive cells on bone surfaces in the parabiosis model used by Boban et al [1] are osteoblast lineage cells is the observation in the paper that while treatment of a non-parabiosed col2.3ΔTK mouse with ganciclovir led to dramatic bone loss, this apparently did not occur in the parabiosis setting. Although these findings are stated only in passing in the results, and no data regarding this potentially very important observation is presented in the paper, it is difficult to envision that transfer of osteoclasts (or osteoclast lineage cells) alone would be sufficient to prevent bone loss following ablation of osteoblasts and bone lining cells.…”

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confidence: 85%

“…Moreover, cells in close proximity to osteoclasts or monocytes (such as bone lining cells) actively endocytose TRAP [6,9]. As such, the GFP-positive cells on the bone surfaces in the models used by Boban and colleagues [1] may be TRAP positive, but these cells (or certainly many of them) may not be osteoclasts and/or monocytes/macrophages.…”

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confidence: 99%

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confidence: 99%

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Letter re: “The 3.6 kb DNA fragment from the rat Col1a1 gene promoter drives the expression of genes in both osteoblast and osteoclast lineage cells” by Boban et al. (Bone 39:1302–1312, 2006)

Khosla

2007

Bone

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In the paper by Boban and colleagues [1], the authors used a parabiosis mouse model to test whether osteoblast-lineage cells traversed the circulation of the parabiosed pair. Using mice expressing GFP driven by the col3.6 promoter, they found that there were GFP-positive cells lining bone surfaces in the non-GFP-expressing parabiosed mouse, indicating extensive transfer of GFP-positive cells. In addition, when they infused Lin − Sca-1 + c-kit + cells from a col3.6-GFP mouse into a non-GFP-expressing mouse, these cells also appeared on bone surfaces as GFP-positive lining cells. However, based on immunohistochemistry for TRAP and in vitro bone marrow cultures, the investigators concluded that the GFP-positive cells lining bone surfaces in the two experiments described above were osteoclasts (or osteoclastlineage cells), and that there was no transfer of osteoblast-lineage cells between the parabiotic pairs or differentiation of the Lin − Sca-1 + c-kit + cells into osteoblastic cells.There are some concerns with the interpretation of the findings, and the authors are perhaps overlooking another important cell type, the bone lining cell, which is likely closely related to the osteoblast, but probably serves a very distinct functional role [2]. The alternate explanation for the findings in this paper are that the GFP-positive cells that are lining the bone surfaces in the parabiosis model and in the mice infused with the Lin − Sca-1 + c-kit + cells are, in fact, bone lining cells. These cells lie in close proximity to osteoclasts [2], express bone-related proteins such as alkaline phosphatase, low levels of osteocalcin and type I collagen (i.e., they are not highly active in synthesizing matrix as are the osteoblasts on bone surfaces), and are also positive for expression of intercellular adhesion molecule-1 (ICAM-1) [2,3], which appears to be necessary for binding to osteoclast precursors and the subsequent support of osteoclastogenesis [4]. By contrast, matrix-synthesizing osteoblasts express high levels of type I collagen and are ICAM-1 negative [2]. Moreover, since bone lining cells lie adherent to bone surfaces, they are unlikely to be present in the bone marrow cultures used in the paper to support the argument that osteoblastic cells did not transfer in the parabiotic mice.

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The 3.6 kb DNA fragment from the rat Col1a1 gene promoter drives the expression of genes in both osteoblast and osteoclast lineage cells

Cited by 52 publications

References 34 publications

Anabolic actions of Notch on mature bone

Anabolic actions of Notch on mature bone

Targeting of androgen receptor in bone reveals a lack of androgen anabolic action and inhibition of osteogenesis

Letter re: “The 3.6 kb DNA fragment from the rat Col1a1 gene promoter drives the expression of genes in both osteoblast and osteoclast lineage cells” by Boban et al. (Bone 39:1302–1312, 2006)

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