Dataset Information

Adult mice lacking the type 2 iodothyronine deiodinase have increased subchondral bone but normal articular cartilage.

ABSTRACT: BACKGROUND:Although osteoarthritis (OA) is the commonest joint disorder and has a rising prevalence as the population ages, no drugs are available that prevent or delay the onset and progression of disease. Recent studies identified the DIO2 gene encoding type 2 deiodinase (D2) as a susceptibility locus for OA, and further data suggest deiodinase-regulated local availability of triiodothyronine (T3) in the joint plays an important role in cartilage maintenance and repair. To investigate the hypothesis that reduced tissue T3 availability protects joints from development of OA, the joint phenotypes of adult mice lacking D2 (D2KO) or lacking both D1 and D2 (D1D2KO), the only enzymes that catalyze conversion of the prohormone thyroxine to active T3, were determined. METHODS:Knee joints were prepared from male 16-week-old adult wild type (WT; n=9), D2KO (n=5), and D1D2KO (n=3) mice. Articular cartilage pathology was scored using the Osteoarthritis Research Society International (OARSI) histopathology scale for murine OA to determine the severity and extent of disease. Digital X-ray microradiography was used to determine the area and mineral content of subchondral bone immediately beneath the articular cartilage surface. RESULTS:There were no differences in maximum and standardized OA scores, cartilage erosion indices, or articular cartilage cellularity among WT, D2KO, and D1D2KO mice. Subchondral bone area did not differ among genotypes, but mineral content was markedly increased in both D2KO and D1D2KO mice compared to WT. CONCLUSIONS:Although adult D2KO mice have normal articular cartilage and no other features of spontaneous joint damage, they exhibit increased subchondral bone mineral content.

SUBMITTER: Waung JA

PROVIDER: S-EPMC4361410 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Adult mice lacking the type 2 iodothyronine deiodinase have increased subchondral bone but normal articular cartilage.

Waung Julian A JA Bassett J H Duncan JH Williams Graham R GR

Thyroid : official journal of the American Thyroid Association 20150203 3

<h4>Background</h4>Although osteoarthritis (OA) is the commonest joint disorder and has a rising prevalence as the population ages, no drugs are available that prevent or delay the onset and progression of disease. Recent studies identified the DIO2 gene encoding type 2 deiodinase (D2) as a susceptibility locus for OA, and further data suggest deiodinase-regulated local availability of triiodothyronine (T3) in the joint plays an important role in cartilage maintenance and repair. To investigate ...[more]

PMID: 25549200

Similar Datasets

Project description:Objective : To study molecular changes in the articular cartilage and subchondral bone of the tibial plateau from mice deficient in frizzled related protein (Frzb) compared to wild-type mice by transcriptome analysis. Methods : Gene-expression analysis of the articular cartilage and subchondral bone of 3 wild-type and 3 Frzb-/- mice was performed by microarray. Pathway analysis of differentially expressed genes between 3 wild-type and 2 Frzb-/- samples was explored with PANTHER, DAVID and GSEA bioinformatics tools. Activation of the WNT pathway was analyzed using western blot. The effects of Frzb gain and loss of function on chondrogenesis and cell proliferation was examined using ATDC5 micromasses and mouse ribcage chondrocytes. Results : Extracellular matrix-associated integrin and cadherin pathways, as well as WNT pathway genes were upregulated in Frzb-/- samples. Several WNT receptors, target genes, and other antagonists were upregulated, but no difference in active β-catenin was found. Analysis of ATDC5 cell micromasses overexpressing FRZB indicated an upregulation of aggrecan and Col2a1, and downregulation of molecules related to damage and repair in cartilage, Col3a1 and Col5a1. Silencing of Frzb resulted in downregulation of aggrecan and Col2a1. Pathways associated with cell cycle were downregulated. Ribcage chondrocytes derived from Frzb-/- mice showed decreased proliferation compared to wild-type cells. Conclusions : Our analysis provides evidence for tight regulation of WNT signaling, shifts in extracellular matrix components and effects on cell proliferation and differentiation in the articular cartilage - subchondral bone unit in Frzb-/- mice. These data further support an important role for FRZB in joint homeostasis and highlight the complex biology of WNT signaling in the joint. Gene-expression analysis of the articular cartilage and subchondral bone of 3 wild-type and 3 Frzb-/- mice was performed by microarray. Pathway analysis of differentially expressed genes between 3 wild-type and 2 Frzb-/- samples was explored with PANTHER, DAVID and GSEA bioinformatics tools.

Project description:ObjectiveKnee osteoarthritis (KOA) is a highly prevalent musculoskeletal disorder characterized by degeneration of cartilage and abnormal remodeling of subchondral bone (SCB). Teriparatide (PTH (1-34)) is an effective anabolic drug for osteoporosis (OP) and regulates osteoprotegerin (OPG)/receptor activator of nuclear factor ligand (RANKL)/RANK signaling, which also has a therapeutic effect on KOA by ameliorating cartilage degradation and inhibiting aberrant remodeling of SCB. However, the mechanisms of PTH (1-34) in treating KOA are still uncertain and remain to be explored. Therefore, we compared the effect of PTH (1-34) on the post-traumatic KOA mouse model to explore the potential therapeutic effect and mechanisms.MethodsIn vivo study, eight-week-old male mice including wild-type (WT) (n = 54) and OPG-/- (n = 54) were investigated and compared. Post-traumatic KOA model was created by destabilization of medial meniscus (DMM). WT mice were randomly assigned into three groups: the sham group (WT-sham; n = 18), the DMM group (WT-DMM; n = 18), and the PTH (1-34)-treated group (WT-DMM + PTH (1-34); n = 18). Similarly, the OPG-/- mice were randomly allocated into three groups as well. The designed mice were executed at the 4th, 8th, and 12th weeks to evaluate KOA progression. To further explore the chondro-protective of PTH (1-34), the ATDC5 chondrocytes were stimulated with different concentrations of PTH (1-34) in vitro.ResultsCompared with the WT-sham mice, significant wear of cartilage in terms of reduced cartilage thickness and glycosaminoglycan (GAG) loss was detected in the WT-DMM mice. PTH (1-34) exhibited cartilage-protective by alleviating wear, retaining the thickness and GAG contents. Moreover, the deterioration of the SCB was alleviated and the expression of PTH1R/OPG/RANKL/RANK were found to increase after PTH (1-34) treatment. Among the OPG-/- mice, the cartilage of the DMM mice displayed typical KOA change with higher OARSI score and thinner cartilage. The damage of the cartilage was alleviated but the abnormal remodeling of SCB didn't show any response to the PTH (1-34) treatment. Compared with the WT-DMM mice, the OPG-/--DMM mice caught more aggressive KOA with thinner cartilage, sever cartilage damage, and more abnormal remodeling of SCB. Moreover, both the damaged cartilage from the WT-DMM mice and the OPG-/--DMM mice were alleviated but only the deterioration of SCB in WT-DMM mice was alleviated after the administration of PTH (1-34). In vitro study, PTH (1-34) could promote the viability of chondrocytes, enhance the synthesis of extracellular matrix (ECM) (AGC, COLII, and SOX9) at the mRNA and protein level, but inhibit the secretion of inflammatory cytokines (TNF-α and IL-6).ConclusionBoth wear of the cartilage was alleviated and aberrant remodeling of the SCB was inhibited in the WT mice, but only the cartilage-protective effect was observed in the OPG-/- mice. PTH (1-34) exhibited chondro-protective effect by decelerating cartilage degeneration in vivo as well as by promoting the proliferation and enhancing ECM synthesis of chondrocytes in vitro. The current investigation implied that the rescue of the disturbed SCB is dependent on the regulation of OPG while the chondro-protective effect is independent of modulation of OPG, which provides proof for the treatment of KOA.The translational potential of this articleSystemic administration of PTH (1-34) could exert a therapeutic effect on both cartilage and SCB in different mechanisms to alleviate KOA progression, which might be a novel therapy for KOA.

Dataset Information

Adult mice lacking the type 2 iodothyronine deiodinase have increased subchondral bone but normal articular cartilage.

Publications

Adult mice lacking the type 2 iodothyronine deiodinase have increased subchondral bone but normal articular cartilage.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets