Histol Histopathol. 2014 May;29(5):609-18.

Induction of high temperature requirement A1, a serine protease, by TGF-beta1 in articular chondrocytes of mouse models of OA.

Xu L1, Golshirazian I2, Asbury BJ2, Li Y3.
  • 1Department of Developmental Biology, Harvard School of Dental Medicine, and Harvard Medical School, Boston MA, USA. lin_xu@hms.harvard.edu.
  • 2Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA.
  • 3Department of Developmental Biology, Harvard School of Dental Medicine, and Harvard Medical School, Boston MA, USA. yefu_li@hms.harvard.edu.

 

Abstract

The goal of this study is to determine whether transforming growth factor beta 1 (Tgf-β1) induces the high temperature requirement A1 (HtrA1) in articular chondrocytes of two mouse models of osteoarthritis (OA). Early onset articular cartilage degeneration in the mouse models was characterized by histology. Expression profiles of Tgf-β1, p-Smad1, p-Smad2/3 and HtrA1 in knee joints of the mouse models were examined by immunofluorescene. By in vitro and ex vivo experiments, human primary chondrocytes and articular cartilages from femoral condyles of mice were treated with recombinant human TGF-β1 and an ALK5 chemical inhibitor, SB431542. The level of HTRA1 mRNA in human and mouse articular chondrocytes was examined by real-time PCR. Chondrocyte clusters were present in the articular cartilage of knee joints in the mouse models. Increased expressions of Tgf-β1, p-Smad2/3 and HtrA1 were detected in the articular chondrocyte of knee joints in the mouse models. The increased expressions of p-Smad2/3 and HtrA1 were co-localized in the articular chondrocyte of the knee joints. The expression of p-Smad1 was hardly detectable in the mouse models and their corresponding wild-type littermates. The level of HTRA1 mRNA was increased in human and mouse articular chondrocytes treated with TGF-β1, compared with that in chondrocytes without the treatment of TGF-β1. The TGF-β1-induced expression of HTRA1 in human and mouse articular chondrocytes was inhibited by SB431542. These results suggest that the Tgf-β1 canonical signaling was activated to induce HtrA1 in the articular chondrocytes of the mouse models of OA.

PMID: 24135912

 

Supplements:

The most pressing issue in osteoarthritis (OA) is development of the disease-modifying OA drugs (DMOADs), as currently there are no such drugs available. The paucity of suitable DMOADs is mostly due to the lack of known therapeutic targets necessary for the development of these drugs. However, based upon recent discoveries from our laboratory and other independent researchers, we strongly believe that several molecules, including transforming growth factor beta 1 (TGF-b1), a serine protease, high temperature requirement A1 (HTRA1), and a cell surface receptor tyrosine kinase for native type II collagen, discoidin domain receptor 2 (DDR2), may be ideal targets for the development of DMOADs. We hypothesize that in adult joints, mechanical stress is the initial insult to stimulate chondrocytes to synthesize and release TGF-β1. The active TGF-β1 binds to its cognate receptor, TGF-β receptor 2, which induces expression of HTRA1 in chondrocytes. Consequences of induction of HTRA1 are degradation of the pericellular matrix of chondrocytes and enhanced exposure of chondrocytes to type II collagen. Interaction of chondrocytes with type II collagen results in enhanced signaling through DDR2. This induces the expression of matrix metalloproteinase 13 (MMP-13), one of the major extracellular matrix degrading enzymes.  MMP-13 degradation of type II collagen and aggrecan results in type II collagen and aggrecan fragments, which in turn may activate signals that further increase the synthesis of MMP-13. The end result is a feedback amplification loop that causes irreversible articular cartilage degeneration. Therefore, drugs that inhibit the activity of TGF- β1, HTRA1 and DDR2 may be able to ameliorate OA conditions in adult joints.

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