Structural Variations in Articular Cartilage Matrix Are Associated with Early-Onset Osteoarthritis in the Spondyloepiphyseal Dysplasia Congenita (Sedc) Mouse

Macdonald, David W.; Squires, Ryan S.; Avery, S.; Adams, Jason S.; Baker, Melissa A.; Cunningham, Christopher; Heimann, Nicholas B.; Kooyman, David L.; Seegmiller, Robert E.

doi:10.3390/ijms140816515

Cited by 16 publications

(13 citation statements)

References 40 publications

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“…Chondrocytes within articular cartilage are surrounded by a pericellular matrix (PCM) which is composed primarily of Type VI collagen and other proteins [13,14,15]. The chondrocyte PCM has a stiffness of ~25–200 kPa [16] which is diminished in OA [17].…”

Section: Introductionmentioning

confidence: 99%

Candidate mediators of chondrocyte mechanotransduction via targeted and untargeted metabolomic measurements

Jutila

Zignego

Hwang

et al. 2014

Archives of Biochemistry and Biophysics

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Chondrocyte mechanotransduction is the process by which cartilage cells transduce mechanical loads into biochemical and biological signals. Previous studies have identified several pathways by which chondrocytes transduce mechanical loads, yet a general understanding of which signals are activated and in what order remains elusive. This study was performed to identify candidate mediators of chondrocyte mechanotransduction using SW1353 chondrocytes embedded in physiologically stiff agarose. Dynamic compression was applied to cell-seeded constructs for 0–30 minutes, followed immediately by whole-cell metabolite extraction. Metabolites were detected via LC-MS, and compounds of interest were identified via database searches. We found several metabolites which were statistically different between the experimental groups, and we report the detection of 5 molecules which are not found in metabolite databases of known compounds indicating potential novel molecules. Targeted studies to quantify the response of central energy metabolites to compression found a transient increase in the ratio of NADP+ to NADPH and a continual decrease in the ratio of GDP to GTP, suggesting a flux of energy into the TCA cycle. These data are consistent with the remodeling of cytoskeletal components by mechanically induced signaling, and add substantial new data to a complex picture of how chondrocytes transduce mechanical loads.

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Section: Introductionmentioning

confidence: 99%

Candidate mediators of chondrocyte mechanotransduction via targeted and untargeted metabolomic measurements

Jutila

Zignego

Hwang

et al. 2014

Archives of Biochemistry and Biophysics

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“…We have also shown that the heterozygous sedc mouse, although morphometrically normal, exhibits early onset OA [9]. This puzzle was solved, in part, when we demonstrated using electron microscopy that compared with controls, mutant articular cartilage displayed decreased fibril diameter concomitant with increases in size of the pericellular space, Mankin and OARSI scores, cartilage thickness, chondrocyte clustering, proteoglycan staining and horizontal fissuring [13]. We concluded that collagen in the mutant's articular cartilage (both heterozygote and homozygote) fails to provide the normal meshwork required for matrix integrity and overall cartilage stability.…”

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confidence: 88%

Collagen Mutant Mouse Models Provide an Important Tool to Study Osteoarthritis

Rose¹,

Seegmiller²,

Bridgewater³

et al. 2016

J Arthritis

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Mutations in the human type II (COL2A1) collagen gene appear to be the basis for many skeletal disorders such as spondyloepiphyseal dysplasia [1], achondrogenesis, Kniest, and Stickler syndrome [2]. Several of these conditions include early-onset osteoarthritis in addition to the chondrodysplasia phenotype [3]. Other collagen genes are also involved etiologically in the chondrodysplasias, e.g., an autosomal dominant form of Stickler syndrome, characterized by mild spondyloepiphyseal dysplasia (SED) and early-onset osteoarthritis, results from a mutation involving the COL11A2 gene that encodes the α2 (XI) chain of the quantitatively minor fibrillar type XI collagen [4]. Multiple epiphyseal dysplasia in humans involving flattening of the epiphyses, shortening of endochondral bones, and early-onset osteoarthritis has been linked to a mutation in type IX collagen [5], and mice made transgenic for α1 (IX) mutation have been shown to develop osteoarthritis and intervertebral disc degeneration prematurely [6]. The Disproportionate micromelia (Dmm) mouse has a mutation that causes lethal dwarfism in the homozygote and mild dwarfism in the heterozygote. This strain of mouse has a threenucleotide deletion in the C-propeptide region of the Col2a1 gene, a gene highly conserved with its human homologue, COL2A1 [7]. Both genes encode for type II collagen, the most abundant protein in hyaline cartilage [8]. As a result of the Col2a1 deletion, Dmm/+ mice have a decrease of proteoglycan production in the hyaline cartilage that typically yields early onset degradation and OA. We have previously reported OA-like changes in a mouse model that bears a mutation in the Col2a1 gene, similar to that found in humans, that behaves as a recessive mutation resulting in no obvious phenotype in the heterozygote [9]. The mouse mutation was named spondyloepiphesial dysplasia congenita (sedc) [10] because when homozygous it produces features that resemble the most common clinical phenotypes of SED congenita in humans [11]. Thus in both mouse and human it is known that collagen gene mutations that lead to a wide variety of disorders of the skeletal system can also lead to premature osteoarthritis.While chondrodysplasia models of OA have been important in advancing our understanding of OA, the majority of OA cases in humans are not associated with any recognizable features of chondrodysplasia. This raises the question of whether the cartilage collagen genes play a significant role in the majority of human OA, or are only relevant in the minority of cases associated with chondrodysplasias. It has been shown that, in fact, at least two different heterozygous point mutations in the triple helical domain of the COL2A1 gene can cause degenerative joint disease in humans in the absence of other phenotypic abnormalities [12]. We have also shown that the heterozygous sedc mouse, although morphometrically normal, exhibits early onset OA [9]. This puzzle was solved, in part, when we demonstrated using electron microscopy that compared with controls, mutant ...

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“…tidemark, in murine knee joints was actually detected with a Safranin-O stain [29], we devised this study. We set out to determine if the delineating tidemark is in fact an area of active metabolic calcification and whether it progresses toward the apical surface of the cartilage as OA progresses.…”

Section: Discussionmentioning

confidence: 99%

“…Mmp-13 is a matrix metalloproteinase that digests Type II collagen and ultimately contributes to the mechanical destabilization of the ECM [29]. Mmp-13 has also been associated with inflammation triggered OA [26,30].…”

Section: Introductionmentioning

confidence: 99%

Identification of the Tidemark Line of Calcification in Osteoarthritic Cartilage Using a Stain for Alkaline Phosphatase

Black¹,

Crepeau²,

Sheffield³

et al. 2017

J Arthritis

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Inflammatory response and calcification are strongly implicated in osteoarthritis (OA) progression. Key inflammatory biomarkers present throughout the process of OA have been established but an association with calcification has not been clarified. A faint line, tidemark, exists between the subchondral bone and the articular surface in knee joints that is presumed to be the line of demarcation between calcified and uncalcified cartilage. This study shows that the tidemark is where calcification is actively occurring. Mouse knees (n=8) were stained for both Alkaline Phosphatase (ALP) and Safranin-O/Fast Green. ALP, active during tissue calcification, was used to identify the true location of calcification. Images from both stains were overlaid for comparison of complementary tissues. The cartilage area above the tidemark was then compared to the area above the ALP line of calcification. Because the two areas proved to be nearly statistically identical, the conclusion is that the tidemark observed in the Safranin-O/Fast Green stain is indeed the line of calcification for articular cartilage. The role of calcification in OA was further examined by comparing NPP1, calcification marker, with HtrA1. We demonstrate a reciprocal correlation between HtrA1 and NPP1, suggesting a link between pathological calcification and inflammation in joints experiencing OA.

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Structural Variations in Articular Cartilage Matrix Are Associated with Early-Onset Osteoarthritis in the Spondyloepiphyseal Dysplasia Congenita (Sedc) Mouse

Cited by 16 publications

References 40 publications

Candidate mediators of chondrocyte mechanotransduction via targeted and untargeted metabolomic measurements

Candidate mediators of chondrocyte mechanotransduction via targeted and untargeted metabolomic measurements

Collagen Mutant Mouse Models Provide an Important Tool to Study Osteoarthritis

Identification of the Tidemark Line of Calcification in Osteoarthritic Cartilage Using a Stain for Alkaline Phosphatase

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