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Updated: Jun 21, 2026
Culturing and Measuring Fetal and Newborn Murine Long Bones
Published on: April 26, 2019
Phosphate regulates embryonic endochondral bone development
Alena A Zalutskaya1, Megan K Cox, Marie B Demay
1Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Insights
High phosphate levels promote embryonic chondrocyte differentiation and apoptosis. This study reveals phosphate
Area of Science:
- Skeletal Biology
- Developmental Biology
- Cell Biology
Background:
- Phosphate is crucial for chondrocyte differentiation and growth plate development.
- High phosphate concentrations activate apoptosis in hypertrophic chondrocytes in vitro.
- The role of extracellular phosphate in embryonic endochondral bone formation is unclear.
Purpose of the Study:
- To investigate the effect of extracellular phosphate on chondrocyte differentiation and apoptosis during embryonic skeletal development.
- To determine if phosphate modulates chondrocyte behavior in the context of endochondral bone formation.
Main Methods:
- Utilized a mouse metatarsal culture model to mimic embryonic bone development.
- Cultured metatarsals with varying phosphate concentrations (1.25 mM and 7 mM) for 4, 8, and 12 days.
- Assessed chondrocyte proliferation, differentiation, FGF18 expression, and caspase-9 activation via immunohistochemistry.
Main Results:
- Higher phosphate (7 mM) reduced chondrocyte proliferation but enhanced hypertrophic differentiation and FGF18 expression.
- Elevated caspase-9 activation and apoptosis were observed in hypertrophic chondrocytes at 7 mM phosphate by day 8.
- Caspase-9 activation in hypertrophic chondrocytes correlated with vascular invasion in embryonic bones.
Conclusions:
- Extracellular phosphate promotes chondrocyte differentiation during embryonic development.
- Phosphate activates the mitochondrial apoptotic pathway in hypertrophic chondrocytes during embryonic endochondral bone formation.
- Phosphate plays a significant physiological role in regulating chondrocyte fate during skeletal development.
Abstract:
Phosphate is required for terminal differentiation of hypertrophic chondrocytes during postnatal growth plate maturation. In vitro models of chondrocyte differentiation demonstrate that 7 mM phosphate, a concentration analogous to that of the late gestational fetus, activates the mitochondrial apoptotic pathway in hypertrophic chondrocytes. This raises the question as to whether extracellular phosphate modulates chondrocyte differentiation and apoptosis during embryonic endochondral bone formation. To address this question, we performed investigations in the mouse metatarsal culture model that recapitulates in vivo bone development. Metatarsals were cultured for 4, 8, and 12 days with 1.25 and 7 mM phosphate. Metatarsals cultured with 7 mM phosphate showed a decrease in proliferation compared to those cultured in 1.25 mM phosphate. This decrease in proliferation was accompanied by an early enhancement in hypertrophic chondrocyte differentiation, associated with an increase in FGF18 expression. By 8 days in culture, an increase caspase-9 activation and apoptosis of hypertrophic chondrocytes was observed in the metatarsals cultured in 7 mM phosphate. Immunohistochemical analyses of embryonic bones demonstrated activation of caspase-9 in hypertrophic chondrocytes, associated with vascular invasion. Thus, these investigations demonstrate that phosphate promotes chondrocyte differentiation during embryonic development and implicate a physiological role for phosphate activation of the mitochondrial apoptotic pathway during embryonic endochondral bone formation.
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