Growth factor regulation of intracellular pH homeostasis under hypoxic conditions in isolated equine articular chondrocytes.
Abstract: Hypoxia and acidosis are recognized features of inflammatory arthroses. This study describes the effects of IGF-1 and TGF-β(1) on pH regulatory mechanisms in articular cartilage under hypoxic conditions. Acid efflux, reactive oxygen species (ROS), and mitochondrial membrane potential were measured in equine articular chondrocytes isolated in the presence of serum (10% fetal calf serum), IGF-1 (1, 10, 50, 100 ng/ml) or TGF-β(1) (0.1, 1, 10 ng/ml) and then exposed to a short-term (3 h) hypoxic insult (1% O(2)). Serum and 100 ng/ml IGF-1 but not TGF-β(1) attenuated hypoxic regulation of pH homeostasis. IGF-1 appeared to act through mitochondrial membrane potential stabilization and maintenance of intracellular ROS levels in very low levels of oxygen. Using protein phosphorylation inhibitors PD98059 (25 µM) and wortmannin (200 nM) and Western blotting, ERK1/2 and PI-3 kinase pathways are important for the effect of IGF-1 downstream to ROS generation in normoxia but only PI-3 kinase is implicated in hypoxia. These results show that oxygen and growth factors interact to regulate pH recovery in articular chondrocytes by modulating intracellular oxygen metabolites.
Copyright © 2012 Orthopaedic Research Society.
Publication Date: 2012-09-14 PubMed ID: 22987771DOI: 10.1002/jor.22221Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The research investigates how growth factors IGF-1 and TGF-β(1) affect pH balance in cartilage cells under low-oxygen conditions, a common issue in joint diseases. The study indicates that IGF-1, but not TGF-β(1), helps maintain pH balance under such conditions, likely by stabilizing mitochondrial potential and regulating build-up of reactive oxygen species.
Objective of the Research
- The research aimed to understand the impacts of insulin-like growth factor-1 (IGF-1) and transforming growth factor-beta 1 (TGF-β(1)) on the regulation of cellular pH in equine articular chondrocytes (cartilage cells) under hypoxic, or low oxygen, conditions. Such conditions are notable features of inflammatory joint disorders.
Methods of the Research
- The researchers collected equine articular chondrocytes and subjected them to a short-term hypoxic situation (3 hours at 1% Oxygen), in the presence of varying levels of IGF-1 or TGF-β(1).
- They measured acid efflux, reactive oxygen species (ROS), and the mitochondrial membrane potential in these conditions, taking into account the presence of serum (10% fetal calf serum).
- The study also used protein phosphorylation inhibitors and western blotting technique to identify the role of ERK1/2 and PI-3 kinase pathways in the observed effects of IGF-1 and TGF-β(1).
Key Findings of the Research
- The study found that serum and high levels of IGF-1 (100 ng/ml) helped maintain the pH balance in chondrocytes under hypoxia, but TGF-β(1) had no such effect.
- The protective effect of IGF-1 was associated with the stabilization of the mitochondrial membrane potential and moderation of intracellular ROS levels under very low oxygen.
- ERK1/2 and PI-3 kinase pathways were identified as crucial in the functions of IGF-1 in regulating pH response; PI-3 kinase specifically was implicated in hypoxic conditions.
- In conclusion, the research revealed that oxygen levels and growth factors interact to regulate pH recovery in cartilage cells by modulating intracellular oxygen metabolites.
Cite This Article
APA
Milner PI, Smith HC, Robinson R, Wilkins RJ, Gibson JS.
(2012).
Growth factor regulation of intracellular pH homeostasis under hypoxic conditions in isolated equine articular chondrocytes.
J Orthop Res, 31(2), 197-203.
https://doi.org/10.1002/jor.22221 Publication
Researcher Affiliations
- Faculty of Health and Life Sciences, Department of Musculoskeletal Biology, University of Liverpool, Leahurst Campus, Neston CH64 7TE, United Kingdom. p.i.milner@liverpool.ac.uk
MeSH Terms
- Acid-Base Equilibrium / drug effects
- Androstadienes / pharmacology
- Animals
- Cartilage, Articular / drug effects
- Chondrocytes / drug effects
- Flavonoids / pharmacology
- Homeostasis / drug effects
- Horses
- Hydrogen-Ion Concentration
- Hypoxia / metabolism
- Insulin-Like Growth Factor I / pharmacology
- MAP Kinase Signaling System / drug effects
- Membrane Potential, Mitochondrial / drug effects
- Oxygen / pharmacology
- Phosphoinositide-3 Kinase Inhibitors
- Phosphorylation / drug effects
- Reactive Oxygen Species / metabolism
- Transforming Growth Factor beta / pharmacology
- Wortmannin
Grant Funding
- Biotechnology and Biological Sciences Research Council
- Wellcome Trust
Citations
This article has been cited 2 times.- Yue D, Du L, Zhang B, Wu H, Yang Q, Wang M, Pan J. Time-dependently Appeared Microenvironmental Changes and Mechanism after Cartilage or Joint Damage and the Influences on Cartilage Regeneration.. Organogenesis 2021 Oct 2;17(3-4):85-99.
- Sánchez JC, López-Zapata DF. Effects of Adipokines and Insulin on Intracellular pH, Calcium Concentration, and Responses to Hypo-Osmolarity in Human Articular Chondrocytes from Healthy and Osteoarthritic Cartilage.. Cartilage 2015 Jan;6(1):45-54.
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