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Review
. 2018 Jan;31(1):1-9.
doi: 10.1007/s13577-017-0182-x. Epub 2017 Sep 15.

HMGB proteins and arthritis

Noboru Taniguchi  1   2 , Yasuhiko Kawakami  3 , Ikuro Maruyama  4 , Martin Lotz  5
Affiliations
Review

HMGB proteins and arthritis

Noboru Taniguchi et al. Hum Cell. 2018 Jan.

Abstract

The high-mobility group box (HMGB) family includes four members: HMGB1, 2, 3 and 4. HMGB proteins have two functions. In the nucleus, HMGB proteins bind to DNA in a DNA structure-dependent but nucleotide sequence-independent manner to function in chromatin remodeling. Extracellularly, HMGB proteins function as alarmins, which are endogenous molecules released upon tissue damage to activate the immune system. HMGB1 acts as a late mediator of inflammation and contributes to prolonged and sustained systemic inflammation in subjects with rheumatoid arthritis. By contrast, Hmgb2 -/- mice represent a relevant model of aging-related osteoarthritis (OA), which is associated with the suppression of HMGB2 expression in cartilage. Hmgb2 mutant mice not only develop early-onset OA but also exhibit a specific phenotype in the superficial zone (SZ) of articular cartilage. Given the similar expression and activation patterns of HMGB2 and β-catenin in articular cartilage, the loss of these pathways in the SZ of articular cartilage may lead to altered gene expression, cell death and OA-like pathogenesis. Moreover, HMGB2 regulates chondrocyte hypertrophy by mediating Runt-related transcription factor 2 expression and Wnt signaling. Therefore, one possible mechanism explaining the modulation of lymphoid enhancer binding factor 1 (LEF1)-dependent transactivation by HMGB2 is that a differential interaction between HMGB2 and nuclear factors affects the transcription of genes containing LEF1-responsive elements. The multiple functions of HMGB proteins reveal the complex roles of these proteins as innate and endogenous regulators of inflammation in joints and their cooperative roles in cartilage hypertrophy as well as in the maintenance of joint tissue homeostasis.

Keywords: HMGB protein; Inflammatory mediator; Osteoarthritis; Rheumatoid arthritis; Wnt signaling.

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Conflict of interest statement

Conflicts of interest

The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Expression of HMGB2, PRG4/SZP and Wnt signaling activity in articular cartilage.
Figure 2
Figure 2
Safranin O staining of the articular cartilage of knee joints from 9-month-old wild-type mice and Hmgb2−/− mice. Hmgb2−/− mice show structural cartilage defects.
Figure 3
Figure 3
The proposed mechanism of osteoarthritis associated with aging-related loss of HMGB2.
Figure 4
Figure 4
Functional and physical interactions between HMGB2, RUNX2, and LEF1 on a promoter containing a TCF/ LEF motif.
See this image and copyright information in PMC

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