Effects of molecular oxygen on chick limb bud chondrogenesis

Hwang, Paul M.; Byrne, Dennis H.; Kitos, Paul A.

doi:10.1111/j.1432-0436.1988.tb00791.x

Cited by 7 publications

(2 citation statements)

References 31 publications

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“…The nuclear receptor RORα is another marker for prehypertrophic and hypertrophic chondrocytes (35) that showed an increase in expression similar to that of p57 in mutant mice (Figure 5C). Similar up‐regulation was observed for HIF‐1α (Figure 5D), a sensor for low oxygen tension (36, 37) that has been implicated in cartilage development (38).…”

Section: Resultssupporting

confidence: 73%

Endothelial nitric oxide synthase deficiency in mice results in reduced chondrocyte proliferation and endochondral bone growth

Qiu

Feng

Beier

2010

Arthritis & Rheumatism

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Objective. Nitric oxide (NO) and aberrant chondrocyte differentiation have both been implicated in the pathogenesis of osteoarthritis, but whether these processes are connected is unknown, and the role of specific NO synthase (NOS) enzymes in chondrocyte physiology is unclear. This study was undertaken to examine the effects of inactivation of endothelial cell NOS (eNOS) on cartilage development in mice.Methods. Skeletal growth and development of mice carrying a null mutation in the eNOS gene was compared with that of their control littermates. In situ analyses were complemented by experiments with primary chondrocytes and tibial explants from these mice.Results. Mice that were deficient in eNOS showed increased fatality and reduced bone growth, with hypocellular growth plates and a marked reduction in the number of proliferating chondrocytes. In vitro studies demonstrated lower chondrocyte numbers and reduced endochondral bone growth in mutant mice, suggesting that the role of eNOS signaling in chondrocyte proliferation is cell autonomous. Reduced chondrocyte numbers appear to be caused by decreased cyclin D1 and increased p57 expression in mutant mice, resulting in slower cell cycle progression and earlier cell cycle exit. In addition, expression of early chondrocyte markers such as SOX9 was reduced, and prehypertrophic markers were expressed prematurely in mutant mice.Conclusion. Our findings identify a novel and important role of eNOS in chondrocyte proliferation and endochondral bone growth and demonstrate that loss of eNOS results in premature cell cycle exit and prehypertrophic chondrocyte differentiation during cartilage development.

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Section: Resultssupporting

confidence: 73%

Endothelial nitric oxide synthase deficiency in mice results in reduced chondrocyte proliferation and endochondral bone growth

Qiu

Feng

Beier

2010

Arthritis & Rheumatism

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“…Finally, high oxygen levels could interfere with chondrogenesis. Studies have shown that high oxygen tension can decrease certain traits of in vitro chondrogenesis (Hwang et al, 1988). In summary, vascular regression may be required to prevent local production and/or release of antichondrogenic factors and molecules, thus creating a microenvironment conducive to chondrogenesis.…”

Section: Discussion Blood Vessels and Chondrogenesismentioning

confidence: 99%

Vascular regression is required for mesenchymal condensation and chondrogenesis in the developing limb

Yin

Pacifici

2001

Developmental Dynamics

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Vascular regression occurs during limb mesenchymal cell condensation and chondrogenesis, but it is unclear whether it is required for these processes or is a secondary phenomenon without major regulatory roles. To address this issue, beads presoaked with the potent angiogenic factor vascular endothelial growth factor (VEGF) were implanted in the vicinity of the prospective digit 2 in early chick embryo wing buds and the effects on angiogenesis and digit development were determined over time. We found that VEGF treatment caused a marked local increase in blood vessel number and density. Strikingly, this was accompanied by inhibition of digit 2 development as revealed by lack of expression of chondrogenic transcription factor Sox9 and absence of Alcian blue staining. Vascular distribution and skeletal development in adjacent areas remained largely unaffected. Inhibition of digit formation and excess vascularization were both reversible upon further embryonic growth and dissipation of VEGF activity. When supernumerary digits were induced at the anterior limb margin by retinoic acid treatment, their development was also preceded by vascular regression; interestingly, cotreatment with VEGF inhibited supernumerary digit development as well. Direct exposure of limb mesenchymal cells in micromass cultures to VEGF caused no obvious effects on condensation and chondrogenesis, indicating that VEGF effects are not due to direct action on skeletal cells. Our results are the first to provide evidence that vascular regression is required for mesenchymal condensation and chondrogenesis. A model of how patterning mechanisms and vascular regression may intersect and orchestrate limb skeletogenesis is proposed.

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Histological and in vitro studies supporting decreased uteroplacental blood flow as explanation for digital defects after administration of vasodilators

Danielsson¹,

Danielson²,

Reiland³

et al. 1990

Teratology

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In a recent study, the vasodilating drugs nifedipine, nitrendipine, felodipine, and hydralazine induced phalangeal defects in rabbits, when given on day 16 of pregnancy. Histologically, the changes were characterized by disturbed chondrogenesis. In order to elucidate mechanisms behind the defects, the fetal concentration of felodipine was measured, and the fetal limb plates were examined histologically, at 0, 2, 4, 8, 12, and 24 hours after single oral administration of felodipine (12 mumol/kg) on day 16 in pregnant rabbits. The effects of nifedipine, nitrendipine, and felodipine were also investigated in an in vitro system, in which chick embryonic mesenchymal limb bud cells differentiated into chondrocytes. In this system, no inhibition of chondrogenesis was observed below concentrations 3 x 10(5) M. At this concentration, unspecific cytotoxicity was found. The highest fetal concentrations of felodipine were more than 500 times lower than what was required for in vitro toxicity. Histologically, the digital areas of the limb plates showed extensive edema and dilatation of marginal sinus within 2 hours. After 8 hours, rupture of the thin-walled vessels occurred with hemorrhages. Finally, small necroses and blisters were observed. Similar early changes have been reported in experiments where digital defects were induced by clamping uterine vessels. This study thus indicates that the phalangeal defects after administration of high doses of vasodilators are secondary to pharmacological action (associated with a significant reduction in the uteroplacental blood flow), and not a direct effect on fetal chondrogenesis.

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Effects of molecular oxygen on chick limb bud chondrogenesis

Cited by 7 publications

References 31 publications

Endothelial nitric oxide synthase deficiency in mice results in reduced chondrocyte proliferation and endochondral bone growth

Endothelial nitric oxide synthase deficiency in mice results in reduced chondrocyte proliferation and endochondral bone growth

Vascular regression is required for mesenchymal condensation and chondrogenesis in the developing limb

Histological and in vitro studies supporting decreased uteroplacental blood flow as explanation for digital defects after administration of vasodilators

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