Age-related matrix stiffening epigenetically regulates α-Klotho expression and compromises chondrocyte integrity PMID: 36627269

ADC Targets in Oncology

2026-04-10

Age-related matrix stiffening epigenetically regulates α-Klotho expression and compromises chondrocyte integrity

Nat Commun. 2023 Jan 10;14(1):18. doi: 10.1038/s41467-022-35359-2.

Hirotaka Iijima ¹ ² ³ , Gabrielle Gilmer ⁴ ⁵ ⁶ ⁷ ⁸ , Kai Wang ⁹ ⁷ ⁸ , Allison C Bean ⁹ ¹⁰ , Yuchen He ¹¹ , Hang Lin ⁵ ¹⁰ ¹¹ , Wan-Yee Tang ¹² , Daniel Lamont ¹³ , Chia Tai ¹⁴ , Akira Ito ¹⁴ , Jeffrey J Jones ¹⁵ , Christopher Evans ¹⁶ , Fabrisia Ambrosio ¹⁷ ¹⁸ ¹⁹ ²⁰ ²¹ ²² ²³

Affiliations

1. Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
2. Japan Society for the Promotion of Science, Tokyo, Japan. [email protected].
3. Institute for Advanced Research, Nagoya University, Nagoya, Japan. [email protected].
4. Medical Scientist Training Program, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
5. Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.
6. Cellular and Molecular Pathology Graduate Program, University of Pittsburgh, Pittsburgh, PA, USA.
7. Discovery Center for Musculoskeletal Recovery, Schoen Adams Research Institute at Spaulding, Boston, MA, USA.
8. Department of Physical Medicine & Rehabilitation, Harvard Medical School, Boston, MA, USA.
9. Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA.
10. McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
11. Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
12. Department of Environmental and Occupational Health, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA.
13. Petersen Institute of Nanoscience and Engineering, University of Pittsburgh, Pittsburgh, PA, USA.
14. Department of Motor Function Analysis, Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
15. Proteome Exploration Laboratory, Beckman Institute, California Institute of Technology, Pasadena, CA, USA.
16. Department of Physical Medicine & Rehabilitation, Mayo Clinic, Rochester, MN, USA.
17. Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
18. Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
19. Discovery Center for Musculoskeletal Recovery, Schoen Adams Research Institute at Spaulding, Boston, MA, USA. [email protected].
20. Department of Physical Medicine & Rehabilitation, Harvard Medical School, Boston, MA, USA. [email protected].
21. McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
22. Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
23. Department of Environmental and Occupational Health, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA. [email protected].

Abstract

Extracellular matrix stiffening is a quintessential feature of cartilage aging, a leading cause of knee osteoarthritis. Yet, the downstream molecular and cellular consequences of age-related biophysical alterations are poorly understood. Here, we show that epigenetic regulation of α-Klotho represents a novel mechanosensitive mechanism by which the aged extracellular matrix influences chondrocyte physiology. Using mass spectrometry proteomics followed by a series of genetic and pharmacological manipulations, we discovered that increased matrix stiffness drove Klotho promoter methylation, downregulated Klotho gene expression, and accelerated chondrocyte senescence in vitro. In contrast, exposing aged chondrocytes to a soft matrix restored a more youthful phenotype in vitro and enhanced cartilage integrity in vivo. Our findings demonstrate that age-related alterations in extracellular matrix biophysical properties initiate pathogenic mechanotransductive signaling that promotes Klotho promoter methylation and compromises cellular health. These findings are likely to have broad implications even beyond cartilage for the field of aging research.