Aging-related loss of the chromatin protein HMGB2 in articular cartilage is linked to reduced cellularity and osteoarthritis

doi:10.1073/pnas.0806062106

Aging-related loss of the chromatin protein HMGB2 in articular cartilage is linked to reduced cellularity and osteoarthritis

^aDivision of Arthritis Research, The Scripps Research Institute, La Jolla, CA 92037;
^bDepartment of Biological and Technological Research, San Raffaele University, 20132 Milan, Italy; and
^cDepartment of Orthopaedic Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520, Japan

Edited by Dennis A. Carson, University of California at San Diego, La Jolla, CA, and approved November 21, 2008 (received for review June 23, 2008)

Abstract

Osteoarthritis (OA) is the most common joint disease and typically begins with an aging-related disruption of the articular cartilage surface. Mechanisms leading to the aging-related cartilage surface degeneration remain to be determined. Here, we demonstrate that nonhistone chromatin protein high-mobility group box (HMGB) protein 2 is uniquely expressed in the superficial zone (SZ) of human articular cartilage. In human and murine cartilage, there is an aging-related loss of HMGB2 expression, ultimately leading to its complete absence. Mice genetically deficient in HMGB2 (Hmgb2^−/−) show earlier onset of and more severe OA. This is associated with a profound reduction in cartilage cellularity attributable to increased cell death. These cellular changes precede glycosaminoglycan depletion and progressive cartilage erosions. Chondrocytes from Hmgb2^−/− mice are more susceptible to apoptosis induction in vitro. In conclusion, HMGB2 is a transcriptional regulator specifically expressed in the SZ of human articular cartilage and supports chondrocyte survival. Aging is associated with a loss of HMGB2 expression and reduced cellularity, and this contributes to the development of OA.

Footnotes

¹To whom correspondence should be addressed at: Division of Arthritis Research, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail: mlotz{at}scripps.edu
Author contributions: N.T. and M.L. designed the study; N.T., B.C., and U.U. performed research; L.R. and M.E.B. generated Hmgb2-deficient mice; N.T. and M.L. analyzed data; and N.T., S.K., M.E.B., and M.L. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.