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Updated: Aug 16, 2026
Chondrogenic Differentiation Induction of Adipose-derived Stem Cells by Centrifugal Gravity
Published on: February 24, 2017
Advanced glycation end-products attenuate human mesenchymal stem cells and prevent cognate differentiation into
Shinichiro Kume1, Seiya Kato, Sho-ichi Yamagishi
1Department of Orthopaedic Surgery, Kurume University School of Medicine, Kurume, Japan.
Unlabelled:
The impact of AGEs on human MSCs was studied. AGEs inhibited the proliferation of MSCs, induced apoptosis, and prevented cognate differentiation into adipose tissue, cartilage, and bone, suggesting a deleterious effect of AGEs in the pathogenesis of musculoskeletal disorders in aged and diabetic patients.
Introduction:
Advanced glycation end-products (AGEs) are accumulated on long-lived proteins of various tissues in advanced age and diabetes mellitus and have been implicated in chronic complication, including musculoskeletal disorders. Human mesenchymal stem cells (MSCs) potentially differentiate into mature musculoskeletal tissues during tissue repair, but the pathogenetic role of AGEs on MSCs is unclear.
Materials And Methods:
AGEs were prepared by incubating BSA with glucose, glyceraldehydes, or glycolaldehyde (designated as AGE-1, AGE-2, or AGE-3, respectively). Proliferation, apoptosis, and reactive oxygen species (ROS) generation were assayed in AGE-treated cells. The expression of the receptor for AGE (RAGE) was examined by immunohistochemistry and Western blotting. Involvement of RAGE-mediated signaling was examined using a neutralizing antiserum against RAGE. Differentiation into adipose tissue, cartilage, and bone were morphologically and biochemically monitored with specific markers for each.
Results:
AGE-2 and AGE-3, but not control nonglycated BSA and AGE-1, reduced the viable cell number and 5-bromo-2'deoxyuridine (BrdU) incorporation with increased intracellular ROS generation and the percentage of apoptotic cells. MSCs expressed RAGE and its induction was stimulated by AGE-2 and AGE-3. These AGEs inhibited adipogenic differentiation (assayed by oil red O staining, lipoprotein lipase production, and intracellular triglyceride content) and chondrogenic differentiation (assayed by safranin O staining and type II collagen production). On osteogenic differentiation, AGE-2 and AGE-3 increased alkaline phosphatase activity and intracellular calcium content; however, von Kossa staining revealed the loss of mineralization and mature bone nodule formation. The antiserum against RAGE partially prevented AGE-induced cellular events.
Conclusion:
AGE-2 and AGE-3 may lead to the in vivo loss of MSC mass and the delay of tissue repair by inhibiting the maturation of MSC-derived cells. The AGE-RAGE interaction may be involved in the deleterious effect of AGEs on MSCs.
Insights
Advanced glycation end-products (AGEs) negatively impact human mesenchymal stem cells (MSCs), hindering their proliferation, promoting apoptosis, and impairing differentiation. This suggests AGEs contribute to musculoskeletal disorders in aged and diabetic individuals.
Area of Science:
- Biochemistry
- Cell Biology
- Biomedical Engineering
Background:
- Advanced glycation end-products (AGEs) accumulate with age and in diabetes, contributing to chronic complications like musculoskeletal disorders.
- Human mesenchymal stem cells (MSCs) are crucial for musculoskeletal tissue repair through differentiation.
- The specific impact of AGEs on MSCs and their pathogenetic role remain unclear.
Purpose of the Study:
- To investigate the effects of AGEs on human MSCs.
- To determine the role of the receptor for AGE (RAGE) in mediating these effects.
- To elucidate the implications for musculoskeletal health in aging and diabetes.
Main Methods:
- Preparation of different AGEs (AGE-1, AGE-2, AGE-3) by incubating BSA with sugars.
- Assay of MSC proliferation, apoptosis, and reactive oxygen species (ROS) generation.
- Examination of RAGE expression and RAGE-mediated signaling.
- Morphological and biochemical assessment of MSC differentiation into adipose, cartilage, and bone tissues.
Main Results:
- Specific AGEs (AGE-2, AGE-3) reduced MSC viability, increased ROS, and induced apoptosis.
- MSCs express RAGE, which is upregulated by AGE-2 and AGE-3.
- AGEs inhibited adipogenic and chondrogenic differentiation.
- AGEs impaired osteogenic differentiation, leading to failed mineralization despite increased alkaline phosphatase and calcium content.
- Neutralizing RAGE partially mitigated AGE-induced cellular effects.
Conclusions:
- AGE-2 and AGE-3 negatively impact MSCs, potentially causing loss of MSC mass and delayed tissue repair.
- The AGE-RAGE interaction is implicated in the detrimental effects of AGEs on MSCs.
- These findings highlight a mechanism contributing to musculoskeletal disorders in aging and diabetic conditions.
