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Altered responsiveness to TGF-? results in reduced Papss2 expression and alterations in the biomechanical properties of mouse articular cartilage.

ABSTRACT: Previous studies have indicated that transforming growth factor ? (TGF-?) signaling has a critical role in cartilage homeostasis and repair, yet the mechanisms of TGF-?'s chondroprotective effects are not known. Our objective in this study was to identify downstream targets of TGF-? that could act to maintain biochemical and biomechanical properties of cartilage.Tibial joints from 20-week-old mice that express a dominant-negative mutation of the TGF-? type II receptor (DNIIR) were graded histologically for osteoarthritic changes and tested by indentation to evaluate their mechanical properties. To identify gene targets of TGF-?, microarray analysis was performed using bovine articular chondrocytes grown in micromass culture that were either treated with TGF-? or left untreated. Phosphoadenosine phosphosynthetase 2 (PAPSS2) was identified as a TGF-?-responsive gene. Papss2 expression is crucial for proper sulfation of cartilage matrix, and its deficiency causes skeletal defects in mice and humans that overlap with those seen in mice with mutations in TGF-?-signaling genes. Regulation of Papss2 was verified by real time RT-PCR and Western blot analyses. Alterations in sulfation of glycosaminoglycans were analyzed by critical electrolyte concentration and Alcian blue staining and immunofluorescence for chondroitin-4-sulfate, unsulfated chondroitin and the aggrecan core protein.DNIIR mutants showed reduced mechanical properties and osteoarthritis-like changes when compared to wild-type control mice. Microarray analysis identified a group of genes encoding matrix-modifying enzymes that were regulated by TGF-?. Papss2 was upregulated in bovine articular chondrocytes after treatment with TGF-? and downregulated in cartilage from DNIIR mice. Articular cartilage in DNIIR mice demonstrated reduced Alcian blue staining at critical electrolyte concentrations and reduced chondroitin-4-sulfate staining. Staining for unsulfated chondroitin sulfate was increased, whereas staining for the aggrecan core protein was comparable in DNIIR and wild-type mice.TGF-? maintains biomechanical properties and regulates expression of Papss2 and sulfation of glycosaminoglycans in mouse articular cartilage.

SUBMITTER: Ramaswamy G

PROVIDER: S-EPMC3446415 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Altered responsiveness to TGF-β results in reduced Papss2 expression and alterations in the biomechanical properties of mouse articular cartilage.

Ramaswamy Girish G Sohn Philip P Eberhardt Alan A Serra Rosa R

Arthritis research & therapy 20120306 2

<h4>Introduction</h4>Previous studies have indicated that transforming growth factor β (TGF-β) signaling has a critical role in cartilage homeostasis and repair, yet the mechanisms of TGF-β's chondroprotective effects are not known. Our objective in this study was to identify downstream targets of TGF-β that could act to maintain biochemical and biomechanical properties of cartilage.<h4>Methods</h4>Tibial joints from 20-week-old mice that express a dominant-negative mutation of the TGF-β type II ...[more]

PMID: 22394585

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Project description:An exact understanding of the interplay between the articulating tissues of the knee joint in relation to the osteoarthritis (OA)-related degeneration process is of considerable interest. Therefore, the aim of the present study was to characterize the biomechanical properties of mildly and severely degenerated human knee joints, including their menisci and tibial and femoral articular cartilage (AC) surfaces. A spatial biomechanical mapping of the articulating knee joint surfaces of 12 mildly and 12 severely degenerated human cadaveric knee joints was assessed using a multiaxial mechanical testing machine. To do so, indentation stress relaxation tests were combined with thickness and water content measurements at the lateral and medial menisci and the AC of the tibial plateau and femoral condyles to calculate the instantaneous modulus (IM), relaxation modulus, relaxation percentage, maximum applied force during the indentation, and the water content. With progressing joint degeneration, we found an increase in the lateral and the medial meniscal instantaneous moduli (p < 0.02), relaxation moduli (p < 0.01), and maximum applied forces (p < 0.01), while for the underlying tibial AC, the IM (p = 0.01) and maximum applied force (p < 0.01) decreased only at the medial compartment. Degeneration had no influence on the relaxation percentage of the soft tissues. While the water content of the menisci did not change with progressing degeneration, the severely degenerated tibial AC contained more water (p < 0.04) compared to the mildly degenerated tibial cartilage. The results of this study indicate that degeneration-related (bio-)mechanical changes seem likely to be first detectable in the menisci before the articular knee joint cartilage is affected. Should these findings be further reinforced by structural and imaging analyses, the treatment and diagnostic paradigms of OA might be modified, focusing on the early detection of meniscal degeneration and its respective treatment, with the final aim to delay osteoarthritis onset.

Dataset Information

Altered responsiveness to TGF-? results in reduced Papss2 expression and alterations in the biomechanical properties of mouse articular cartilage.

Publications

Altered responsiveness to TGF-β results in reduced Papss2 expression and alterations in the biomechanical properties of mouse articular cartilage.

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