AN N-terminal peptide from link protein stimulates proteoglycan biosynthesis in human articular cartilage in vitro

McKenna, Louise A.; Liu, Hongxiang; Sansom, Paul A.; Dean, Michael F.

doi:10.1002/1529-0131(199801)41:1<157::aid-art19>3.0.co;2-j

Cited by 53 publications

(42 citation statements)

References 16 publications

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“…In addition, recent findings indicate that LP, or at least its N-terminal domain, may function as a growth factor up-regulating the synthesis of aggrecan and type II collagen in cartilage (21)(22)(23)(24).…”

Section: In Brainmentioning

confidence: 85%

“…These "rescued" mice with ϳ50% of the wild type level of cartilage LP not only survived but grew normally without skeletal deformities. These findings may be related to the cartilage growth factor characteristics of LP (21)(22)(23)54). A peptide of 16 amino acids, cleaved from the N-terminal end of cartilage LP, can function as a growth factor and is able to stimulate the expression of aggrecan (22,23) and type II collagen (54).…”

Section: Discussionmentioning

confidence: 98%

“…These findings may be related to the cartilage growth factor characteristics of LP (21)(22)(23)54). A peptide of 16 amino acids, cleaved from the N-terminal end of cartilage LP, can function as a growth factor and is able to stimulate the expression of aggrecan (22,23) and type II collagen (54). This N-terminal peptide of LP may be involved in the homeostatic regulation and synthesis of matrix components during the normal turn- Newborn (Aa and Ee; less than 1 day old), 4 days old (Bb and Ff), 3 weeks old (Cc and Gg), and adult mice (Dd and Hh) are shown.…”

Section: Discussionmentioning

confidence: 99%

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Genetic Rescue of Chondrodysplasia and the Perinatal Lethal Effect of Cartilage Link Protein Deficiency

Czipri

Otto

Cs‐Szabó

et al. 2003

Journal of Biological Chemistry

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The targeted disruption of cartilage link protein gene (Crtl1) in homozygous mice resulted in a severe chondrodysplasia and perinatal lethality. This raised the question of whether the abnormalities seen in Crtl1 null mice are all caused by the absence of link protein in cartilage or whether the deficiency of the protein in other tissues and organs contributed to the phenotype. To address this question we have generated transgenic mice overexpressing cartilage link protein under the control of a cartilage-specific promoter, and then these transgenic mice were used for a genetic rescue of abnormalities in Crtl1 null mice. While the overexpression of cartilage link protein resulted in no abnormal phenotype, the cartilage-specific transgene expression of link protein could completely prevent the perinatal mortality of link protein-deficient mice and, depending on the level of the link protein expression, rescue skeletal abnormalities. Although link protein was originally isolated from cartilage, we found and determined Crtl1 transcripts and corresponding proteins in every organ tested from mouse embryos to aging animals. We also identified three additional members of the link protein family, all co-localized with hyaluronic acid-binding proteoglycans in the mouse genome. The ubiquitous presence of link protein suggests a general and systemic function of link protein in the organization of extracellular matrix in a number of tissues, possibly interacting with other proteoglycans, such as versican, brevican, and neurocan.A highly specific macromolecular organization of cartilage extracellular matrix (ECM) 1 is required for chondrogenesis, chondrocyte differentiation, endochondral ossification, and for the maintenance of the weight-bearing function of articular cartilage. The major macromolecular components of this ECM are the proteoglycan aggrecan, hyaluronic acid (hyaluronan, HA), link protein (LP) and type II collagen. Hundreds of aggrecan molecules associate with a single HA filament to form large proteoglycan aggregates. The link protein, a glycoprotein, binding simultaneously to both HA and aggrecan, stabilizes the aggregate structure (1), and the aggregates are entrapped within the mesh-like network of type II collagen fibrils (2-4). The negatively charged glycosaminoglycan chains of aggrecan bind large amounts of water and are responsible for the resiliency of cartilage (5). Mutation in a gene encoding components of cartilage ECM may result in skeletal disorders, chondrodysplasias, in mice (6, 7) and humans (8).Cartilage LP is a member of the hyaluronectin superfamily, and shares a high degree of sequence homology in different species, particularly in the HA binding domain (2), also known as "link module" (4, 9). Although LP was originally isolated from cartilage, its presence has been reported in numerous non-cartilaginous tissues, such as aorta (10), mesonephros, and other embryonic tissues (11, 12), brain (13) and sclera (14) in chicken, and the mouse cumulus-oocyte complex, without concomitant expression...

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Section: In Brainmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Genetic Rescue of Chondrodysplasia and the Perinatal Lethal Effect of Cartilage Link Protein Deficiency

Czipri

Otto

Cs‐Szabó

et al. 2003

Journal of Biological Chemistry

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“…Cartilage-specific transgene expression of CRTL1 can completely prevent perinatal mortality in CRTL1-null mice and rescue skeletal abnormalities at levels dependent upon the amount of CRT-LP expression (6). In addition, CRT-LP may function as a growth factor to up-regulate the synthesis of aggrecan and type II collagen in cartilage (7). Thus, production of CRT-LP at appropriate levels is crucial to the formation of proteoglycan aggregates and the normal organization of hypertrophic chondrocytes.…”

Section: From the Laboratory For Bone And Joint Diseases Snp Researcmentioning

confidence: 99%

SOX9-dependent and -independent Transcriptional Regulation of Human Cartilage Link Protein

Kou¹,

Ikegawa²

2004

Journal of Biological Chemistry

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Cartilage link protein is a key component of the cartilage extracellular matrix. The transcriptional regulation of the gene encoding cartilage link protein (CRTL1) is largely unknown, however. Here, we investigated the regulation of CRTL1 by SOX9, a key regulator of cartilage matrix genes and chondrogenesis. Knockdown of SOX9 resulted in decreased CRTL1 expression. SOX9 induced CRTL1 expression effectively in human nonchondrocytic immortalized cell lines as well as in mesenchymal stem cell and adult dermal fibroblast. These results indicate that, like other cartilage matrix genes, SOX9 is a key regulator of CRTL1. Unlike other cartilage matrix genes, however, the activation of CRTL1 by SOX9 and its known transcriptional co-activators L-SOX5 and SOX6 was cell type-dependent. Two cis-acting enhancer elements resided in the 5-untranslated region of CRTL1. One contained a heptameric SOX binding sequence and showed SOX9-dependent enhancer activity in several cell lines. The other showed cell type-specific SOX9-independent enhancer activity. These findings suggest that the enhancer elements may mediate differential expression of CRTL1 during chondrocyte differentiation and maturation.

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“…In addition, a synthetic peptide of HAPLN1 stimulates the biosynthesis of collagens II, IX, and proteoglycan in the intervertebral disc cells [15]. HAPLN1 may function as a growth factor that upregulates the synthesis of aggrecan and type II collagen in cartilage [12]. HAPLN1 mRNA expression is upregulated by SOX9, a key regulator of cartilage matrix genes and chondrogenesis, and is downregulated in osteoarthritic cartilage [10,22].…”

Section: Introductionmentioning

confidence: 98%

Single-nucleotide polymorphism in the hyaluronan and proteoglycan link protein 1 (HAPLN1) gene is associated with spinal osteophyte formation and disc degeneration in Japanese women

Urano

Narusawa

Shiraki³

et al. 2010

Eur Spine J

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Spinal osteoarthritis including disc degeneration is a very common condition in the axial skeletons of aged people. Recently, spinal osteoarthritis has been shown to be influenced by specific genetic risk factors. Vertebral osteophytes, endplate sclerosis, and intervertebral disc narrowing are recognized as radiographic features of spinal disc degeneration. HAPLN1 is a key component of the cartilage extracellular matrix; thus, variations in this gene may affect the pathogenesis of cartilage-related diseases such as spinal degeneration. Here, we examine the association between an HAPLN1 gene polymorphism and the radiographic features of spinal degeneration. We evaluated the degree of endplate sclerosis, osteophyte formation, and disc space narrowing in 622 Japanese postmenopausal women. Four SNPs in the HAPLN1 gene-in the 5 0 flanking region, intron 1, intron 2, and intron 4-were analyzed using the TaqMan polymerase chain reaction method. We found that compared to subjects with the CC or CT genotype, those with the TT genotype for an SNP at intron 2 (rs179851) were significantly overrepresented among the subjects with higher scores for osteophyte formation (P = 0.0001; odds ratio 2.12; 95% confidence interval 1.45-3.11, as determined by logistic regression analysis) and disc space narrowing (P = 0.0057; odds ratio 1.83; 95% confidence interval 1.19-2.83). Consistent with the involvement of the HAPLN1 gene in cartilage metabolism, a variation in a specific HAPLN1 gene locus may be associated with spinal degeneration.

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AN N-terminal peptide from link protein stimulates proteoglycan biosynthesis in human articular cartilage in vitro

Cited by 53 publications

References 16 publications

Genetic Rescue of Chondrodysplasia and the Perinatal Lethal Effect of Cartilage Link Protein Deficiency

Genetic Rescue of Chondrodysplasia and the Perinatal Lethal Effect of Cartilage Link Protein Deficiency

SOX9-dependent and -independent Transcriptional Regulation of Human Cartilage Link Protein

Single-nucleotide polymorphism in the hyaluronan and proteoglycan link protein 1 (HAPLN1) gene is associated with spinal osteophyte formation and disc degeneration in Japanese women

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