Role of the Subchondral Vascular System in Endochondral Ossification: Endothelial Cells Specifically Derepress Late Differentiation in Resting Chondrocytesin Vitro

Bittner, K; Vischer, Peter; Bartholmes, Peter; Brückner, Peter

doi:10.1006/excr.1997.3849

Cited by 58 publications

(41 citation statements)

References 35 publications

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“…Dexamethasone can induce mineralization in MSCs by activating Runx2 expression through the (WNT/b-catenin) signaling pathway. [18][19][20] However, in this coculture model, the Runx2 expression is likely produced by chondrocytes within the cellular aggregates, which undergo hypertrophy because of the addition of endothelial cells to the cartilage template, 73 as seen in the collagen type X staining in our previous study. 49 Moreover, the formation of mineralization nodules in the aggregates cultured in osteogenic supplements might be explained by the use of dexamethasone within the osteogenic medium, as similar results have been reported in costochondral chondrocyte cultures exposed to dexamethasone.…”

Section: Discussionmentioning

confidence: 70%

Osteogenic Differentiation of Mesenchymal Stem Cells by Mimicking the Cellular Niche of the Endochondral Template

Freeman

Stevens

Owens

et al. 2016

Tissue Engineering Part A

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In vitro bone regeneration strategies that prime mesenchymal stem cells (MSCs) with chondrogenic factors, to mimic aspects of the endochondral ossification process, have been shown to promote mineralization and vascularization by MSCs both in vitro and when implanted in vivo. However, these approaches required the use of osteogenic supplements, namely dexamethasone, ascorbic acid, and b-glycerophosphate, none of which are endogenous mediators of bone formation in vivo. Rather MSCs, endothelial progenitor cells, and chondrocytes all reside in proximity within the cartilage template and might paracrineally regulate osteogenic differentiation. Thus, this study tests the hypothesis that an in vitro bone regeneration approach that mimics the cellular niche existing during endochondral ossification, through coculture of MSCs, endothelial cells, and chondrocytes, will obviate the need for extraneous osteogenic supplements and provide an alternative strategy to elicit osteogenic differentiation of MSCs and mineral production. The specific objectives of this study were to (1) mimic the cellular niche existing during endochondral ossification and (2) investigate whether osteogenic differentiation could be induced without the use of any external growth factors. To test the hypothesis, we evaluated the mineralization and vessel formation potential of (a) a novel methodology involving both chondrogenic priming and the coculture of human umbilical vein endothelial cells (HUVECs) and MSCs compared with (b) chondrogenic priming of MSCs alone, (c) addition of HUVECs to chondrogenically primed MSC aggregates, (d-f) the same experimental groups cultured in the presence of osteogenic supplements and (g) a noncoculture group cultured in the presence of osteogenic growth factors alone. Biochemical (DNA, alkaline phosphatase [ALP], calcium, CD31 + , vascular endothelial growth factor [VEGF]), histological (alcian blue, alizarin red), and immunohistological (CD31 + ) analyses were conducted to investigate osteogenic differentiation and vascularization at various time points (1, 2, and 3 weeks). The coculture methodology enhanced both osteogenesis and vasculogenesis compared with osteogenic differentiation alone, whereas osteogenic supplements inhibited the osteogenesis and vascularization (ALP, calcium, and VEGF) induced through coculture alone. Taken together, these results suggest that chondrogenic and vascular priming can obviate the need for osteogenic supplements to induce osteogenesis of human MSCs in vitro, while allowing for the formation of rudimentary vessels.

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Section: Discussionmentioning

confidence: 70%

Osteogenic Differentiation of Mesenchymal Stem Cells by Mimicking the Cellular Niche of the Endochondral Template

Freeman

Stevens

Owens

et al. 2016

Tissue Engineering Part A

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“…Tissue vascularisation represents a highly important step during the transition from hypertrophic cartilage to bone during the endochondral ossification of cartilage growth plates [81]. The formation of neovasculature is also likely to be of key importance for the progression of HO, since the formation of bone requires a rich vascular network.…”

Section: Endoderm Endothelial Cellsmentioning

confidence: 99%

“…Endothelial cells have been shown to have a definite indirect contribution to HO, with the production of paracrine factors leading to chondrocyte hypertrophy and matrix ossification [81]. Recent evidence published by identified that Ang1/Tie2 signalling in MSC cultures led to a strongly osteochondrogenic phenotype, further identifying a link between endothelial cells and the pathological process of ectopic bone formation [85].…”

Section: Endoderm Endothelial Cellsmentioning

confidence: 99%

Identifying the Cellular Mechanisms Leading to Heterotopic Ossification

et al. 2015

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“…The antler is unique and informative in that the angiogenesis is not directly associated with calcification. The discovery that during endochondral ossification endothelial cells can regulate the process of chondrogenesis, in particular the progression of chondrocytes into a hypertrophic phenotype (Bittner et al, 1998), raises questions of whether endothelial cell signaling is substantively different in the antler or whether the regulation of chondrogenesis is markedly different.…”

Section: Discussionmentioning

confidence: 99%

Vascular localization and proliferation in the growing tip of the deer antler

Clark

Wang

et al. 2006

Anat. Rec.

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The process of angiogenesis is of interest because of the significant clinical benefits associated with controlling vascular growth. Within the antler, chondrogenesis and antler elongation are occurring at the rate of 1-2 cm per day and thus blood vessels are growing at this same rapid pace. We demonstrate that the process of angiogenesis in the antler is controlled at various tissue locations. The findings clearly differentiate the spatial location of the stem cells that drive chondrogenesis from the proliferation process driving the angiogenesis. Vessels within the lateral dermis contained BrdU-positive cells, suggesting that these vessels were elongating. Within the precartilage region, proliferating vessels were detected in bundles of complex structure evenly distributed throughout this tissue layer. The support cells within these bundles of vessels were detected by staining with a-smooth muscle actin, while the endothelial cells were negative. Additionally, the a-smooth muscle actin staining was found in association with the cartilage cells of the antler. The marked proliferation of the vascular associated cells in the precartilage region identified this area as a major region of vascular growth in the antler. We propose that within the precartilage region, the most likely mechanisms to explain the observed vascular morphology are that of vascular extension of the existing vessels and intussusceptive angiogenesis or sprouting to generate the small bundles of vessels. Anat Rec Part A, 288A: 973-981, 2006.2006 Wiley-Liss, Inc.

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Role of the Subchondral Vascular System in Endochondral Ossification: Endothelial Cells Specifically Derepress Late Differentiation in Resting Chondrocytesin Vitro

Cited by 58 publications

References 35 publications

Osteogenic Differentiation of Mesenchymal Stem Cells by Mimicking the Cellular Niche of the Endochondral Template

Osteogenic Differentiation of Mesenchymal Stem Cells by Mimicking the Cellular Niche of the Endochondral Template

Identifying the Cellular Mechanisms Leading to Heterotopic Ossification

Vascular localization and proliferation in the growing tip of the deer antler

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