Phosphate-induced chondrocyte apoptosis is linked to nitric oxide generation

Teixeira, Cristina; Mansfield, Kyle D.; Hertkorn, Caryn; Ischiropoulos, Harry; Shapiro, Irving M.

doi:10.1152/ajpcell.2001.281.3.c833

Cited by 65 publications

(36 citation statements)

References 43 publications

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“…Chondrocyte hypertrophy in chicken growth plates is accompanied by a loss of thiol, which is thought to increase susceptibility to apoptosis in response to oxidative stress (17,18). Studies in chicken growth plates also demonstrated a maturation-dependent change in mitochondrial morphology accompanied by a decrease in staining with rhodamine 123, a fluorescent dye that binds to the mitochondrial membrane and inhibits transport (19).…”

Section: Discussionmentioning

confidence: 99%

Phosphate-induced Apoptosis of Hypertrophic Chondrocytes Is Associated with a Decrease in Mitochondrial Membrane Potential and Is Dependent upon Erk1/2 Phosphorylation

Miedlich

Zalutskaya

Zhu

et al. 2010

Journal of Biological Chemistry

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Growth plate abnormalities, associated with impaired hypertrophic chondrocyte apoptosis, are observed in humans and animals with abnormalities of vitamin D action and renal phosphate reabsorption. Low circulating phosphate levels impair hypertrophic chondrocyte apoptosis, whereas treatment of these cells with phosphate activates the mitochondrial apoptotic pathway. Because phosphate-mediated apoptosis of chondrocytes is differentiation-dependent, studies were performed to identify factors that contribute to hypertrophic chondrocyte apoptosis. An increase in the percentage of cells with low mitochondrial membrane potential, evaluated by JC-1 fluorescence, was observed during hypertrophic differentiation of primary murine chondrocytes in culture. This percentage was further increased by treatment of hypertrophic, but not proliferative, chondrocytes with phosphate. Phosphate-mediated apoptosis was observed as early as 30 min post-treatment and was dependent upon Erk1/2 phosphorylation. Inhibition of Erk1/2 phosphorylation in vivo confirmed an important role for this signaling pathway in regulating hypertrophic chondrocyte apoptosis in growing mice. Murine embryonic metatarsals cultured under phosphate-restricted conditions demonstrated a 2.5-fold increase in parathyroid hormone-related protein mRNA expression accompanied by a marked attenuation in phospho-Erk immunoreactivity in hypertrophic chondrocytes. Thus, these investigations point to an important role for phosphate in regulating mitochondrial membrane potential in hypertrophic chondrocytes and growth plate maturation by the parathyroid hormone-related protein signaling pathway.Maturation of the growth of long bones is dependent upon the differentiation of proliferative chondrocytes into prehypertrophic and subsequently hypertrophic chondrocytes. Terminal differentiation of hypertrophic chondrocytes is characterized by the expression of signaling molecules that promote vascular invasion, apoptosis, and replacement of hypertrophic chondrocytes by osteoblasts that lay down the primary spongiosa of bone. Aberrant regulation of this developmental process results in growth plate disorders. Although calcium has been shown to play an important role in regulating chondrocyte maturation (1), apoptosis of terminally differentiated hypertrophic chondrocytes is dependent upon normal levels of circulating phosphate (2).Rickets is a growth plate anomaly observed in growing animals and humans with abnormalities of vitamin D action and renal phosphate reabsorption (3-6). In vivo investigations in genetically modified and dietary-manipulated mouse models demonstrate that hypophosphatemia is the underlying metabolic abnormality that impairs growth plate maturation in these disorders: low circulating phosphate levels result in impaired apoptosis of terminally differentiated hypertrophic chondrocytes in the growth plate, leading to rickets (2). The observation that inhibition of phosphate transport prevents phosphate-mediated apoptosis in hypertrophic chondrocytes (7-9) further ...

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Section: Discussionmentioning

confidence: 99%

Phosphate-induced Apoptosis of Hypertrophic Chondrocytes Is Associated with a Decrease in Mitochondrial Membrane Potential and Is Dependent upon Erk1/2 Phosphorylation

Miedlich

Zalutskaya

Zhu

et al. 2010

Journal of Biological Chemistry

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“…There are two main ways that NO sensitizes chondrocytes to apoptosis: decreases the thiol reserve [86] and affects the survival of the cell under oxidative or nitrosative tension. Furthermore, NO decreases mitochondrial membrane potential, which causes a loss of tight coupling, an essential prerequisite for generating ATP by means of oxidative phosphorylation.…”

Section: Regulation Of Differentiationmentioning

confidence: 99%

“…Furthermore, NO decreases mitochondrial membrane potential, which causes a loss of tight coupling, an essential prerequisite for generating ATP by means of oxidative phosphorylation. Interference with mitochondrial activity causes a loss of ATP production leading to a low energy state, which makes chondrocytes more susceptible to enter apoptosis [86]. NO also interferes with cellular adhesion to the extracellular membrane.…”

Section: Regulation Of Differentiationmentioning

confidence: 99%

Morphology and physiology of the epiphyseal growth plate.

Burdan

Szumiło²,

Korobowicz³

et al. 2009

Folia Histochem Cytobiol.

124

108

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Mammalian growth plate, also known as epiphyseal plate or physis, is highly specialized mesodermderived cartilaginous structure. It develops in the bone bud, secondary to presence of the primary ossification centers and is responsible for bone elongation. The plates are formed by numerous cells that rapidly divide and mature. Post puberty, the epiphyseal cartilage cell division decreases, bone completely replaces cartilage, and the epiphyseal plates fuse together with primary and secondary ossification centers [1,2]. Cartilage differentiation processPresently, four major stages of chondrocyte differentiation are known, i.a., mesenchymal precursor cells (MPCs), prechondrocytes, early chondroblasts and terminally differentiated chondrocytes [1][2][3][4]. Abstract: The epiphyseal growth plate develops from the cartilaginous-orientated mesenchymal cells that express SOX family genes. This multilayer structure is formed by the proliferation and hypertrophy of cells that synthesize the extracellular matrix composed of collagen (mainly type II, IX, X, XI) and proteoglycans (aggrecan, decorin, annexin II, V and VI). The resting zone is responsible for protein synthesis and maintaining a germinal structure. In the proliferative zone, cells rapidly duplicate. The subsequent morphological changes take place in the transformation zone, divided into the upper and lower hypertrophic layers. In the degenerative zone, the mineralization process becomes intensive due to increased release of alkaline phosphate, calcium and matrix vesicles by terminally differentiated chondrocytes and some other factors e.g., metaphyseal ingrowth vessels. At this level, as well as in the primary and secondary spongiosa zones, chondrocytes undergo apoptosis and are physiologically eliminated. Unlike adult cartilage, in fetal and early formed growth plates, unusual forms such as autophagal bodies, paralysis and dark chondrocytes are also observed. Their ultrastructure differs greatly from apoptotic and normal cartilage cells. Chondrocyte proliferation and differentiation are regulated by various endocrine, paracrine, and autocrine agents such as growth, thyroid and sex hormones, beta-catenin, bone morphogenetic proteins, insulin-like growth factor, iodothyronine deiodinase, leptin, nitric oxide, transforming growth factor beta and vitamin D metabolites. However, the most significant factor is parathyroid hormone-related protein (PTHrP) which is synthesized in the perichondrium by terminally differentiated chondrocytes. Secondary to activation of PTH/PTHrP receptors, PTHrP stimulates cell proliferation by G protein activation and delays their transformation into prehypertrophic and hypertrophic chondrocytes. When proliferation is completed, chondrocytes release Indian hedgehog (Ihh), which stimulates PTHrP synthesis via a feedback loop. Any disturbances of the epiphyseal development and its physiology result in various skeletal abnormalities known as dysplasia.

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“…Although pharmacological manipulation of NO levels has been shown to affect chondrocyte differentiation (Teixeira et al, 2005;Teixeira et al, 2001), the roles and regulation of individual NOS genes in cartilage development are largely unknown. iNOS is capable of producing large amounts of NO, often in response to extracellular signals, such as pro-inflammatory cytokines (Teixeira et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Inducible nitric oxide synthase–nitric oxide signaling mediates the mitogenic activity of Rac1 during endochondral bone growth

Wang

Qiu

Woods

et al. 2011

Journal of Cell Science

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SummaryCoordinated proliferation and differentiation of growth plate chondrocytes controls endochondral bone growth and final height in humans, and disruption of this process results in diseases of the growing and adult skeleton, such as chondrodysplasias or osteoarthritis. We had shown recently that chondrocyte-specific deletion of the gene Rac1 in mice leads to severe dwarfism due to reduced chondrocyte proliferation, but the molecular pathways involved remained unclear. Here, we demonstrate that Rac1-deficient chondrocytes have severely reduced levels of inducible nitric oxide synthase (iNOS) protein and nitric oxide (NO) production. NO donors reversed the proliferative effects induced by Rac1 deficiency, whereas inhibition of NO production mimicked the effects of Rac1 loss of function. Examination of the growth plate of iNOS-deficient mice revealed reduced chondrocyte proliferation and expression of cyclin D1, resembling the phenotype of Rac1-deficient growth plates. Finally, we demonstrate that Rac1-NO signaling inhibits the expression of ATF3, a known suppressor of cyclin D1 expression in chondrocytes. In conclusion, our studies identify the iNOS-NO pathway as a novel mediator of mitogenic Rac1 signaling and indicate that it could be a target for growth disorder therapies.

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Phosphate-induced chondrocyte apoptosis is linked to nitric oxide generation

Cited by 65 publications

References 43 publications

Phosphate-induced Apoptosis of Hypertrophic Chondrocytes Is Associated with a Decrease in Mitochondrial Membrane Potential and Is Dependent upon Erk1/2 Phosphorylation

Phosphate-induced Apoptosis of Hypertrophic Chondrocytes Is Associated with a Decrease in Mitochondrial Membrane Potential and Is Dependent upon Erk1/2 Phosphorylation

Morphology and physiology of the epiphyseal growth plate.

Inducible nitric oxide synthase–nitric oxide signaling mediates the mitogenic activity of Rac1 during endochondral bone growth

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