Ablation of Perlecan Domain 1 Heparan Sulfate Reduces Progressive Cartilage Degradation, Synovitis, and Osteophyte Size in a Preclinical Model of Posttraumatic Osteoarthritis

Objective To investigate the role of the heparan sulfate (HS) proteoglycan perlecan (HSPG‐2) in regulating fibroblast growth factor (FGF) activity, bone and joint growth, and the onset and progression of posttraumatic osteoarthritis (OA) in a mouse gene‐knockout model. Methods Maturational changes w...

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Published inArthritis & rheumatology (Hoboken, N.J.) Vol. 68; no. 4; pp. 868 - 879
Main Authors Shu, Cindy C., Jackson, Miriam T., Smith, Margaret M., Smith, Susan M., Penm, Steven, Lord, Megan S., Whitelock, John M., Little, Christopher B., Melrose, James
Format Journal Article
LanguageEnglish
Published United States Wiley Subscription Services, Inc 01.04.2016
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Abstract Objective To investigate the role of the heparan sulfate (HS) proteoglycan perlecan (HSPG‐2) in regulating fibroblast growth factor (FGF) activity, bone and joint growth, and the onset and progression of posttraumatic osteoarthritis (OA) in a mouse gene‐knockout model. Methods Maturational changes were evaluated histologically in the knees of 3‐, 6‐, and 12‐week‐old wild‐type (WT) mice and Hspg2Δ3−/Δ3− mice (Hspg2 lacking domain 1 HS, generated by ablation of exon 3 of perlecan). Cartilage damage, subchondral bone sclerosis, osteophytosis, and synovial inflammation were scored at 4 and 8 weeks after surgical induction of OA in WT and Hspg2Δ3−/Δ3− mice. Changes in cartilage expression of FGF‐2, FGF‐18, HSPG‐2, FGF receptor 1 (FGFR‐1), and FGFR‐3 were examined immunohistochemically. Femoral head cartilage from both mouse genotypes was cultured in the presence or absence of interleukin‐1α (IL‐1α), FGF‐2, and FGF‐18, and the content and release of glycosaminoglycan (GAG) and expression of messenger RNA (mRNA) for key matrix molecules, enzymes, and inhibitors were quantified. Results No effect of perlecan HS ablation on growth plate or joint development was detected. After induction of OA, Hspg2Δ3−/Δ3− mice had significantly reduced cartilage erosion, osteophytosis, and synovitis. OA‐induced loss of chondrocyte expression of FGF‐2, FGF‐18, and HSPG‐2 occurred in both genotypes. Expression of FGFR‐1 after OA induction was maintained in WT mice, while FGFR‐3 loss after OA induction was significantly reduced in Hspg2Δ3−/Δ3− mice. There were no genotypic differences in GAG content or release between unstimulated control cartilage and IL‐1α–stimulated cartilage. However, IL‐1α–induced cartilage expression of Mmp3 mRNA was significantly reduced in Hspg2Δ3−/Δ3− mice. Cartilage GAG release in either the presence or absence of IL‐1α was unaltered by FGF‐2 in both genotypes. In cartilage cultures with FGF‐18, IL‐1α–stimulated GAG loss was significantly reduced only in Hspg2Δ3−/Δ3− mice, and this was associated with maintained expression of Fgfr3 mRNA and reduced expression of Mmp2/Mmp3 mRNA. Conclusion Perlecan HS has significant roles in directing the development of posttraumatic OA, potentially via the alteration of FGF/HS/FGFR signaling. These data suggest that the chondroprotection conferred by perlecan HS ablation could be attributed, at least in part, to the preservation of FGFR‐3 and increased FGF signaling.
AbstractList To investigate the role of the heparan sulfate (HS) proteoglycan perlecan (HSPG-2) in regulating fibroblast growth factor (FGF) activity, bone and joint growth, and the onset and progression of posttraumatic osteoarthritis (OA) in a mouse gene-knockout model. Maturational changes were evaluated histologically in the knees of 3-, 6-, and 12-week-old wild-type (WT) mice and Hspg2(Δ3-/Δ3-) mice (Hspg2 lacking domain 1 HS, generated by ablation of exon 3 of perlecan). Cartilage damage, subchondral bone sclerosis, osteophytosis, and synovial inflammation were scored at 4 and 8 weeks after surgical induction of OA in WT and Hspg2(Δ3-/Δ3-) mice. Changes in cartilage expression of FGF-2, FGF-18, HSPG-2, FGF receptor 1 (FGFR-1), and FGFR-3 were examined immunohistochemically. Femoral head cartilage from both mouse genotypes was cultured in the presence or absence of interleukin-1α (IL-1α), FGF-2, and FGF-18, and the content and release of glycosaminoglycan (GAG) and expression of messenger RNA (mRNA) for key matrix molecules, enzymes, and inhibitors were quantified. No effect of perlecan HS ablation on growth plate or joint development was detected. After induction of OA, Hspg2(Δ3-/Δ3-) mice had significantly reduced cartilage erosion, osteophytosis, and synovitis. OA-induced loss of chondrocyte expression of FGF-2, FGF-18, and HSPG-2 occurred in both genotypes. Expression of FGFR-1 after OA induction was maintained in WT mice, while FGFR-3 loss after OA induction was significantly reduced in Hspg2(Δ3-/Δ3-) mice. There were no genotypic differences in GAG content or release between unstimulated control cartilage and IL-1α-stimulated cartilage. However, IL-1α-induced cartilage expression of Mmp3 mRNA was significantly reduced in Hspg2(Δ3-/Δ3-) mice. Cartilage GAG release in either the presence or absence of IL-1α was unaltered by FGF-2 in both genotypes. In cartilage cultures with FGF-18, IL-1α-stimulated GAG loss was significantly reduced only in Hspg2(Δ3-/Δ3-) mice, and this was associated with maintained expression of Fgfr3 mRNA and reduced expression of Mmp2/Mmp3 mRNA. Perlecan HS has significant roles in directing the development of posttraumatic OA, potentially via the alteration of FGF/HS/FGFR signaling. These data suggest that the chondroprotection conferred by perlecan HS ablation could be attributed, at least in part, to the preservation of FGFR-3 and increased FGF signaling.
Objective To investigate the role of the heparan sulfate (HS) proteoglycan perlecan (HSPG-2) in regulating fibroblast growth factor (FGF) activity, bone and joint growth, and the onset and progression of posttraumatic osteoarthritis (OA) in a mouse gene-knockout model. Methods Maturational changes were evaluated histologically in the knees of 3-, 6-, and 12-week-old wild-type (WT) mice and Hspg2[Delta]3-/[Delta]3- mice (Hspg2 lacking domain 1 HS, generated by ablation of exon 3 of perlecan). Cartilage damage, subchondral bone sclerosis, osteophytosis, and synovial inflammation were scored at 4 and 8 weeks after surgical induction of OA in WT and Hspg2[Delta]3-/[Delta]3- mice. Changes in cartilage expression of FGF-2, FGF-18, HSPG-2, FGF receptor 1 (FGFR-1), and FGFR-3 were examined immunohistochemically. Femoral head cartilage from both mouse genotypes was cultured in the presence or absence of interleukin-1[alpha] (IL-1[alpha]), FGF-2, and FGF-18, and the content and release of glycosaminoglycan (GAG) and expression of messenger RNA (mRNA) for key matrix molecules, enzymes, and inhibitors were quantified. Results No effect of perlecan HS ablation on growth plate or joint development was detected. After induction of OA, Hspg2[Delta]3-/[Delta]3- mice had significantly reduced cartilage erosion, osteophytosis, and synovitis. OA-induced loss of chondrocyte expression of FGF-2, FGF-18, and HSPG-2 occurred in both genotypes. Expression of FGFR-1 after OA induction was maintained in WT mice, while FGFR-3 loss after OA induction was significantly reduced in Hspg2[Delta]3-/[Delta]3- mice. There were no genotypic differences in GAG content or release between unstimulated control cartilage and IL-1[alpha]-stimulated cartilage. However, IL-1[alpha]-induced cartilage expression of Mmp3 mRNA was significantly reduced in Hspg2[Delta]3-/[Delta]3- mice. Cartilage GAG release in either the presence or absence of IL-1[alpha] was unaltered by FGF-2 in both genotypes. In cartilage cultures with FGF-18, IL-1[alpha]-stimulated GAG loss was significantly reduced only in Hspg2[Delta]3-/[Delta]3- mice, and this was associated with maintained expression of Fgfr3 mRNA and reduced expression of Mmp2/Mmp3 mRNA. Conclusion Perlecan HS has significant roles in directing the development of posttraumatic OA, potentially via the alteration of FGF/HS/FGFR signaling. These data suggest that the chondroprotection conferred by perlecan HS ablation could be attributed, at least in part, to the preservation of FGFR-3 and increased FGF signaling.
Objective To investigate the role of the heparan sulfate (HS) proteoglycan perlecan (HSPG‐2) in regulating fibroblast growth factor (FGF) activity, bone and joint growth, and the onset and progression of posttraumatic osteoarthritis (OA) in a mouse gene‐knockout model. Methods Maturational changes were evaluated histologically in the knees of 3‐, 6‐, and 12‐week‐old wild‐type (WT) mice and Hspg2Δ3−/Δ3− mice (Hspg2 lacking domain 1 HS, generated by ablation of exon 3 of perlecan). Cartilage damage, subchondral bone sclerosis, osteophytosis, and synovial inflammation were scored at 4 and 8 weeks after surgical induction of OA in WT and Hspg2Δ3−/Δ3− mice. Changes in cartilage expression of FGF‐2, FGF‐18, HSPG‐2, FGF receptor 1 (FGFR‐1), and FGFR‐3 were examined immunohistochemically. Femoral head cartilage from both mouse genotypes was cultured in the presence or absence of interleukin‐1α (IL‐1α), FGF‐2, and FGF‐18, and the content and release of glycosaminoglycan (GAG) and expression of messenger RNA (mRNA) for key matrix molecules, enzymes, and inhibitors were quantified. Results No effect of perlecan HS ablation on growth plate or joint development was detected. After induction of OA, Hspg2Δ3−/Δ3− mice had significantly reduced cartilage erosion, osteophytosis, and synovitis. OA‐induced loss of chondrocyte expression of FGF‐2, FGF‐18, and HSPG‐2 occurred in both genotypes. Expression of FGFR‐1 after OA induction was maintained in WT mice, while FGFR‐3 loss after OA induction was significantly reduced in Hspg2Δ3−/Δ3− mice. There were no genotypic differences in GAG content or release between unstimulated control cartilage and IL‐1α–stimulated cartilage. However, IL‐1α–induced cartilage expression of Mmp3 mRNA was significantly reduced in Hspg2Δ3−/Δ3− mice. Cartilage GAG release in either the presence or absence of IL‐1α was unaltered by FGF‐2 in both genotypes. In cartilage cultures with FGF‐18, IL‐1α–stimulated GAG loss was significantly reduced only in Hspg2Δ3−/Δ3− mice, and this was associated with maintained expression of Fgfr3 mRNA and reduced expression of Mmp2/Mmp3 mRNA. Conclusion Perlecan HS has significant roles in directing the development of posttraumatic OA, potentially via the alteration of FGF/HS/FGFR signaling. These data suggest that the chondroprotection conferred by perlecan HS ablation could be attributed, at least in part, to the preservation of FGFR‐3 and increased FGF signaling.
OBJECTIVETo investigate the role of the heparan sulfate (HS) proteoglycan perlecan (HSPG-2) in regulating fibroblast growth factor (FGF) activity, bone and joint growth, and the onset and progression of posttraumatic osteoarthritis (OA) in a mouse gene-knockout model.METHODSMaturational changes were evaluated histologically in the knees of 3-, 6-, and 12-week-old wild-type (WT) mice and Hspg2(Δ3-/Δ3-) mice (Hspg2 lacking domain 1 HS, generated by ablation of exon 3 of perlecan). Cartilage damage, subchondral bone sclerosis, osteophytosis, and synovial inflammation were scored at 4 and 8 weeks after surgical induction of OA in WT and Hspg2(Δ3-/Δ3-) mice. Changes in cartilage expression of FGF-2, FGF-18, HSPG-2, FGF receptor 1 (FGFR-1), and FGFR-3 were examined immunohistochemically. Femoral head cartilage from both mouse genotypes was cultured in the presence or absence of interleukin-1α (IL-1α), FGF-2, and FGF-18, and the content and release of glycosaminoglycan (GAG) and expression of messenger RNA (mRNA) for key matrix molecules, enzymes, and inhibitors were quantified.RESULTSNo effect of perlecan HS ablation on growth plate or joint development was detected. After induction of OA, Hspg2(Δ3-/Δ3-) mice had significantly reduced cartilage erosion, osteophytosis, and synovitis. OA-induced loss of chondrocyte expression of FGF-2, FGF-18, and HSPG-2 occurred in both genotypes. Expression of FGFR-1 after OA induction was maintained in WT mice, while FGFR-3 loss after OA induction was significantly reduced in Hspg2(Δ3-/Δ3-) mice. There were no genotypic differences in GAG content or release between unstimulated control cartilage and IL-1α-stimulated cartilage. However, IL-1α-induced cartilage expression of Mmp3 mRNA was significantly reduced in Hspg2(Δ3-/Δ3-) mice. Cartilage GAG release in either the presence or absence of IL-1α was unaltered by FGF-2 in both genotypes. In cartilage cultures with FGF-18, IL-1α-stimulated GAG loss was significantly reduced only in Hspg2(Δ3-/Δ3-) mice, and this was associated with maintained expression of Fgfr3 mRNA and reduced expression of Mmp2/Mmp3 mRNA.CONCLUSIONPerlecan HS has significant roles in directing the development of posttraumatic OA, potentially via the alteration of FGF/HS/FGFR signaling. These data suggest that the chondroprotection conferred by perlecan HS ablation could be attributed, at least in part, to the preservation of FGFR-3 and increased FGF signaling.
Objective To investigate the role of the heparan sulfate (HS) proteoglycan perlecan (HSPG-2) in regulating fibroblast growth factor (FGF) activity, bone and joint growth, and the onset and progression of posttraumatic osteoarthritis (OA) in a mouse gene-knockout model. Methods Maturational changes were evaluated histologically in the knees of 3-, 6-, and 12-week-old wild-type (WT) mice and Hspg2 super( Delta 3-/ Delta 3-) mice (Hspg2 lacking domain 1 HS, generated by ablation of exon 3 of perlecan). Cartilage damage, subchondral bone sclerosis, osteophytosis, and synovial inflammation were scored at 4 and 8 weeks after surgical induction of OA in WT and Hspg2 super( Delta 3-/ Delta 3-) mice. Changes in cartilage expression of FGF-2, FGF-18, HSPG-2, FGF receptor 1 (FGFR-1), and FGFR-3 were examined immunohistochemically. Femoral head cartilage from both mouse genotypes was cultured in the presence or absence of interleukin-1 alpha (IL-1 alpha ), FGF-2, and FGF-18, and the content and release of glycosaminoglycan (GAG) and expression of messenger RNA (mRNA) for key matrix molecules, enzymes, and inhibitors were quantified. Results No effect of perlecan HS ablation on growth plate or joint development was detected. After induction of OA, Hspg2 super( Delta 3-/ Delta 3-) mice had significantly reduced cartilage erosion, osteophytosis, and synovitis. OA-induced loss of chondrocyte expression of FGF-2, FGF-18, and HSPG-2 occurred in both genotypes. Expression of FGFR-1 after OA induction was maintained in WT mice, while FGFR-3 loss after OA induction was significantly reduced in Hspg2 super( Delta 3-/ Delta 3-) mice. There were no genotypic differences in GAG content or release between unstimulated control cartilage and IL-1 alpha -stimulated cartilage. However, IL-1 alpha -induced cartilage expression of Mmp3 mRNA was significantly reduced in Hspg2 super( Delta 3-/ Delta 3-) mice. Cartilage GAG release in either the presence or absence of IL-1 alpha was unaltered by FGF-2 in both genotypes. In cartilage cultures with FGF-18, IL-1 alpha -stimulated GAG loss was significantly reduced only in Hspg2 super( Delta 3-/ Delta 3-) mice, and this was associated with maintained expression of Fgfr3 mRNA and reduced expression of Mmp2/Mmp3 mRNA. Conclusion Perlecan HS has significant roles in directing the development of posttraumatic OA, potentially via the alteration of FGF/HS/FGFR signaling. These data suggest that the chondroprotection conferred by perlecan HS ablation could be attributed, at least in part, to the preservation of FGFR-3 and increased FGF signaling.
Author Jackson, Miriam T.
Shu, Cindy C.
Melrose, James
Lord, Megan S.
Smith, Margaret M.
Smith, Susan M.
Penm, Steven
Whitelock, John M.
Little, Christopher B.
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  organization: Kolling Institute, Northern Sydney Local Health District, and the University of Sydney at Royal North Shore Hospital
BackLink https://www.ncbi.nlm.nih.gov/pubmed/26636652$$D View this record in MEDLINE/PubMed
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2016, American College of Rheumatology.
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Notes Drs. Little and Melrose contributed equally to this work.
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Snippet Objective To investigate the role of the heparan sulfate (HS) proteoglycan perlecan (HSPG‐2) in regulating fibroblast growth factor (FGF) activity, bone and...
To investigate the role of the heparan sulfate (HS) proteoglycan perlecan (HSPG-2) in regulating fibroblast growth factor (FGF) activity, bone and joint...
Objective To investigate the role of the heparan sulfate (HS) proteoglycan perlecan (HSPG-2) in regulating fibroblast growth factor (FGF) activity, bone and...
OBJECTIVETo investigate the role of the heparan sulfate (HS) proteoglycan perlecan (HSPG-2) in regulating fibroblast growth factor (FGF) activity, bone and...
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SubjectTerms Animals
Blotting, Western
Cartilage, Articular - metabolism
Cartilage, Articular - pathology
Disease Progression
Fibroblast Growth Factor 2 - metabolism
Fibroblast Growth Factors - metabolism
Gene Expression Profiling
Glycosaminoglycans - metabolism
Heparan sulfate
Heparan Sulfate Proteoglycans - genetics
Heparan Sulfate Proteoglycans - metabolism
Immunohistochemistry
Knee Injuries - complications
Matrix Metalloproteinase 2 - genetics
Matrix Metalloproteinase 3 - genetics
Mice
Mice, Knockout
Organ Size
Osteoarthritis, Knee - etiology
Osteoarthritis, Knee - genetics
Osteoarthritis, Knee - pathology
Osteophyte - etiology
Osteophyte - genetics
Osteophyte - pathology
Osteosclerosis - etiology
Osteosclerosis - genetics
Osteosclerosis - pathology
Receptor, Fibroblast Growth Factor, Type 1 - metabolism
Receptor, Fibroblast Growth Factor, Type 3 - genetics
Receptor, Fibroblast Growth Factor, Type 3 - metabolism
RNA, Messenger - metabolism
Rodents
Synovitis - etiology
Synovitis - genetics
Synovitis - pathology
Title Ablation of Perlecan Domain 1 Heparan Sulfate Reduces Progressive Cartilage Degradation, Synovitis, and Osteophyte Size in a Preclinical Model of Posttraumatic Osteoarthritis
URI https://onlinelibrary.wiley.com/doi/abs/10.1002%2Fart.39529
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Volume 68
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