Phosphate regulates embryonic endochondral bone development

Zalutskaya, Alena; Cox, Megan K.; Demay, Marie B.

doi:10.1002/jcb.22302

Cited by 15 publications

(13 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results also suggest that the disruption of cellular P i homeostasis causes abnormal endochondral ossification due to a reduction of ATP synthesis in Hyp mice. In support of our study, Zalutskaya et al (32) have recently described that P i activates mitochondrial apoptotic pathways and promotes endochondral ossification.…”

Section: Discussionsupporting

confidence: 91%

Cellular ATP Synthesis Mediated by Type III Sodium-dependent Phosphate Transporter Pit-1 Is Critical to Chondrogenesis

Sugita

Kawai²,

Hayashibara

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Disturbed endochondral ossification in X-linked hypophosphatemia indicates an involvement of P i in chondrogenesis.We studied the role of the sodium-dependent P i cotransporters (NPT), which are a widely recognized regulator of cellular P i homeostasis, and the downstream events in chondrogenesis using Hyp mice, the murine homolog of human X-linked hypophosphatemia. Hyp mice showed reduced apoptosis and mineralization in hypertrophic cartilage. Hyp chondrocytes in culture displayed decreased apoptosis and mineralization compared with WT chondrocytes, whereas glycosaminoglycan synthesis, an early event in chondrogenesis, was not altered. Expression of the type III NPT Pit-1 and P i uptake were diminished, and intracellular ATP levels were also reduced in parallel with decreased caspase-9 and caspase-3 activity in Hyp chondrocytes. The competitive NPT inhibitor phosphonoformic acid and ATP synthesis inhibitor 3-bromopyruvate disturbed endochondral ossification with reduced apoptosis in vivo and suppressed apoptosis and mineralization in conjunction with reduced P i uptake and ATP synthesis in WT chondrocytes. Overexpression of Pit-1 in Hyp chondrocytes reversed P i uptake and ATP synthesis and restored apoptosis and mineralization. Our results suggest that cellular ATP synthesis consequent to P i uptake via Pit-1 plays an important role in chondrocyte apoptosis and mineralization, and that chondrogenesis is ATP-dependent.Endochondral ossification is critical to the development and growth of mammals. The process begins with condensation of undifferentiated mesenchymal cells, and these cells differentiate into proliferating chondrocytes that express type II, IX, and XI collagen and sulfated glycosaminoglycans (GAG) 2 (1). Proliferating chondrocytes further differentiate into hypertrophic chondrocytes expressing type X collagen, undergo apoptosis, mineralize, and are ultimately replaced by bone. Disturbance of the endochondral ossification leads to a variety of skeletal disorders.The genetic disease X-linked hypophosphatemia (XLH) is the most common form of inherited rickets in humans and is related to the dominant disorder of P i homeostasis (2). XLH has been shown to be caused by inactive mutations of the PHEX gene and characterized by hypophosphatemia secondary to renal P i wasting, growth retardation due to disturbed endochondral ossification, osteomalacia resulting from reduced mineralization, and abnormally regulated vitamin D metabolism (3). Hyp mice also display similar biochemical and phenotypic abnormalities to human XLH, including hypophosphatemia, osteomalacia, and skeletal abnormalities. Hyp mice thus are a mouse homolog of human XLH (4). Previous studies reported that Hyp mice exhibited disorganized hypertrophic cartilage with reduced apoptotic chondrocytes and hypomineralization (5). We have reported previously that osteoclast number was decreased in Hyp mice compared with WT mice and that a high-P i diet partially restored this, showing that P i influences osteoclastogenesis and suggesting that this P...

show abstract

Section: Discussionsupporting

confidence: 91%

Cellular ATP Synthesis Mediated by Type III Sodium-dependent Phosphate Transporter Pit-1 Is Critical to Chondrogenesis

Sugita

Kawai²,

Hayashibara

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Hypertrophic chondrocyte apoptosis is first seen at the time of vascular invasion in E14.5 humeri, suggesting that vascular invasion is required for hypertrophic chondrocyte apoptosis (Zalutskaya et al, 2009). Consistent with this hypothesis, the hypertrophic chondrocytes of avascular cultured metatarsals do not undergo apoptosis under normal culture conditions, implicating circulating factors, including phosphate, in the induction of hypertrophic chondrocyte apoptosis in vivo (Zalutskaya et al, 2009). Impaired vascular invasion in the growth plates of c-Raf f/f ; ColII-Cre + mice would be expected to attenuate the exposure of hypertrophic chondrocytes to extracellular phosphate, resulting in a decrease in Erk1/2 phosphorylation and in hypertrophic chondrocyte apoptosis.…”

Section: Discussionmentioning

confidence: 99%

C-Raf promotes Angiogenesis during Normal Growth Plate Maturation

et al. 2015

Self Cite

View full text Add to dashboard Cite

Extracellular phosphate plays a key role in growth plate maturation by inducing Erk1/2 (Mapk3/1) phosphorylation, leading to hypertrophic chondrocyte apoptosis. The Raf kinases induce Mek1/2 (Map2k1/2) and Erk1/2 phosphorylation; however, a role for Raf kinases in endochondral bone formation has not been identified. Ablation of both A-Raf (Araf) and B-Raf (Braf) in chondrocytes does not alter growth plate maturation. Because c-Raf (Raf1) phosphorylation is increased by extracellular phosphate and c-Raf is the predominant isoform expressed in hypertrophic chondrocytes, chondrocyte-specific c-Raf knockout mice (c-Raf(f/f);ColII-Cre(+)) were generated to define a role for c-Raf in growth plate maturation. In vivo studies demonstrated that loss of c-Raf in chondrocytes leads to expansion of the hypertrophic layer of the growth plate, with decreased phospho-Erk1/2 immunoreactivity and impaired hypertrophic chondrocyte apoptosis. However, cultured hypertrophic chondrocytes from these mice did not exhibit impairment of phosphate-induced Erk1/2 phosphorylation. Studies performed to reconcile the discrepancy between the in vitro and in vivo hypertrophic chondrocyte phenotypes revealed normal chondrocyte differentiation in c-Raf(f/f);ColII-Cre(+) mice and lack of compensatory increase in the expression of A-Raf and B-Raf. However, VEGF (Vegfa) immunoreactivity in the hypertrophic chondrocytes of c-Raf(f/f);ColII-Cre(+) mice was significantly reduced, associated with increased ubiquitylation of VEGF protein. Thus, c-Raf plays an important role in growth plate maturation by regulating vascular invasion, which is crucial for replacement of terminally differentiated hypertrophic chondrocytes by bone.

show abstract

“…Studies found that FGF18 induced chondrocyte hypertrophy and mineralization [42, 43], while FGF9 inhibited terminal differentiation of calvaria-derived cells and mineralization [44, 45]. FGF7 was a potent inhibitor of phosphate transport [46].…”

Section: Discussionmentioning

confidence: 99%

Biological Activities of Phosphocitrate: A Potential Meniscal Protective Agent

Sun

Roberts

Mauerhan

et al. 2013

BioMed Research International

View full text Add to dashboard Cite

Phosphocitrate (PC) inhibited meniscal calcification and the development of calcium crystal-associated osteoarthritis (OA) in Hartley guinea pigs. However, the mechanisms remain elusive. This study sought to examine the biological activities of PC in the absence of calcium crystals and test the hypothesis that PC is potentially a meniscal protective agent. We found that PC downregulated the expression of many genes classified in cell proliferation, ossification, prostaglandin metabolic process, and wound healing, including bloom syndrome RecQ helicase-like, cell division cycle 7 homolog, cell division cycle 25 homolog C, ankylosis progressive homolog, prostaglandin-endoperoxide synthases-1/cyclooxygenase-1, and plasminogen activator urokinase receptor. In contrast, PC stimulated the expression of many genes classified in fibroblast growth factor receptor signaling pathway, collagen fibril organization, and extracellular structure organization, including fibroblast growth factor 7, collagen type I, alpha 1, and collagen type XI, alpha 1. Consistent with its effect on the expression of genes classified in cell proliferation, collagen fibril organization, and ossification, PC inhibited the proliferation of OA meniscal cells and meniscal cell-mediated calcification while stimulating the production of collagens. These findings indicate that PC is potentially a meniscal-protective agent and a disease-modifying drug for arthritis associated with severe meniscal degeneration.

show abstract

Phosphate regulates embryonic endochondral bone development

Cited by 15 publications

References 26 publications

Cellular ATP Synthesis Mediated by Type III Sodium-dependent Phosphate Transporter Pit-1 Is Critical to Chondrogenesis

Cellular ATP Synthesis Mediated by Type III Sodium-dependent Phosphate Transporter Pit-1 Is Critical to Chondrogenesis

C-Raf promotes Angiogenesis during Normal Growth Plate Maturation

Biological Activities of Phosphocitrate: A Potential Meniscal Protective Agent

Contact Info

Product

Resources

About