Faculty Profiles - AOYAMA Eriko

Papers - AOYAMA Eriko

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Novel role of CCN3 that maintains the differentiated phenotype of articular cartilage

Danilo Janune, Tarek Abd El Kader, Eriko Aoyama, Takashi Nishida, Yasuhiko Tabata, Satoshi Kubota, Masaharu Takigawa

JOURNAL OF BONE AND MINERAL METABOLISM 35 ( 6 ) 582 - 597 2017.11

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

Knowledge of the microenvironment of articular cartilage in health and disease is the key to accomplishing fundamental disease-modifying treatments for osteoarthritis. The proteins comprising the CCN Family are matricellular proteins with a remarkable relevance within the context of cartilage metabolism. CCN2 displays a great capability for regenerating articular cartilage, and CCN3 has been shown to activate the expression of genes related to articular chondrocytes and to repress genes related to endochondral ossification in epiphyseal chondrocytes. Moreover, mice lacking CCN3 protein have been shown to display ostearthritic changes in their knee articular cartilage. In this study, we employed a monoiodoacetic acid (MIA)-induced osteoarthritic model to investigate whether osteoarthritic changes in the cartilage are reciprocally accompanied by CCN3 down-regulation and an inducible overexpression system to evaluate the effects of CCN3 on articular chondrocytes in vitro. Finally, we also investigated the effects of exogenous CCN3 in vivo during the early stages of MIA-induced osteoarthritis. We discovered that CCN3 is expressed by articular chondrocytes in normal rat knees, whereas it is rapidly down-regulated in osteoarthritic knees. In vitro, we also discovered that CCN3 increases the proteoglycan accumulation, the gene expression of type II collagen, tenascin-C and lubricin, as well as the protein production of tenascin-C and lubricin in articular chondrocytes. In vivo, it was discovered that exogenous CCN3 increased tidemark integrity and produced an increased production of lubricin protein. The potential utility of CCN3 as a future therapeutic agent and possible strategies to improve its therapeutic functions are also discussed.

DOI： 10.1007/s00774-016-0793-4

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A Tumor Suppressor Gene Product, Platelet-Derived Growth Factor Receptor-Like Protein Controls Chondrocyte Proliferation and Differentiation Reviewed

Kazumi Kawata, Satoshi Kubota, Takanori Eguchi, Eriko Aoyama, Norifumi H. Moritani, Morihiko Oka, Harumi Kawaki, Masaharu Takigawa

JOURNAL OF CELLULAR BIOCHEMISTRY 118 ( 11 ) 4033 - 4044 2017.11

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

The platelet-derived growth factor receptor-like (PDGFRL) gene is regarded as a tumor suppressor gene. However, nothing is known about the molecular function of PDGFRL. In this study, we initially clarified its function in chondrocytes. Among all cell lines examined, the PDGFRL mRNA level was the highest in chondrocytic HCS-2/8 cells. Interestingly, the proliferation of chondrocytic HCS-2/8 cells was promoted by PDGFRL overexpression, whereas that of the breast cancer-derived MDA-MB-231 cells was inhibited. Of note, in PDGFRL-overexpressing HCS-2/8 cells, the expression of chondrocyte differentiation marker genes, SOX9, ACAN, COL2A1, COL10A1, and ALP, was decreased. Moreover, we confirmed the expression of PDGFRL mRNA in normal cartilage tissue and chondrocytes. Eventually, the expression of PDGFRL mRNA in condrocytes except in the case of hypertrophic chondrocytes was demonstrated in vivo and in vitro. These findings suggest that PDGFRL plays the different roles, depending upon cell types. Particularly, in chondrocytes, PDGFRL may play a new and important role which is distinct from the function previously reported. J. Cell. Biochem. 118: 4033-4044, 2017. (c) 2017 Wiley Periodicals, Inc.

DOI： 10.1002/jcb.26059

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Catabolic effects of FGF-1 on chondrocytes and its possible role in osteoarthritis

Abdellatif El-Seoudi, Tarek Abd El Kader, Takashi Nishida, Takanori Eguchi, Eriko Aoyama, Masaharu Takigawa, Satoshi Kubota

JOURNAL OF CELL COMMUNICATION AND SIGNALING 11 ( 3 ) 255 - 263 2017.9

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Fibroblast growth factor 1 (FGF-1) is a classical member of the FGF family and is produced by chondrocytes cultured from osteoarthritic patients. Also, this growth factor was shown to bind to CCN family protein 2 (CCN2), which regenerates damaged articular cartilage and counteracts osteoarthritis (OA) in an animal model. However, the pathophysiological role of FGF-1 in cartilage has not been well investigated. In this study, we evaluated the effects of FGF-1 in vitro and its production in vivo by use of an OA model. Treatment of human chondrocytic cells with FGF-1 resulted in marked repression of genes for cartilaginous extracellular matrix components, whereas it strongly induced matrix metalloproteinase 13 (MMP-13), representing its catabolic effects on cartilage. Interestingly, expression of the CCN2 gene was dramatically repressed by FGF-1, which repression eventually caused the reduced production of CCN2 protein from the chondrocytic cells. The results of a reporter gene assay revealed that this repression could be ascribed, at least in part, to transcriptional regulation. In contrast, the gene expression of FGF-1 was enhanced by exogenous FGF-1, indicating a positive feedback system in these cells. Of note, induction of FGF-1 was observed in the articular cartilage of a rat OA model. These results collectively indicate a pathological role of FGF-1 in OA development, which includes an insufficient cartilage regeneration response caused by CCN2 down regulation.

DOI： 10.1007/s12079-017-0384-8

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UPR transducer BBF2H7 allows export of type II collagen in a cargo- and developmental stage-specific manner

Tokiro Ishikawa, Takuya Toyama, Yuki Nakamura, Kentaro Tamada, Hitomi Shimizu, Satoshi Ninagawa, Tetsuya Okada, Yasuhiro Kamei, Tomoko Ishikawa-Fujiwara, Takeshi Todo, Eriko Aoyama, Masaharu Takigawa, Akihiro Harada, Kazutoshi Mori

JOURNAL OF CELL BIOLOGY 216 ( 6 ) 1761 - 1774 2017.6

Language：English Publishing type：Research paper (scientific journal) Publisher：ROCKEFELLER UNIV PRESS

The unfolded protein response (UPR) handles unfolded/misfolded proteins accumulated in the endoplasmic reticulum (ER). However, it is unclear how vertebrates correctly use the total of ten UPR transducers. We have found that ER stress occurs physiologically during early embryonic development in medaka fish and that the smooth alignment of notochord cells requires ATF6 as a UPR transducer, which induces ER chaperones for folding of type VIII (short-chain) collagen. After secretion of hedgehog for tissue patterning, notochord cells differentiate into sheath cells, which synthesize type II collagen. In this study, we show that this vacuolization step requires both ATF6 and BBF2H7 as UPR transducers and that BBF2H7 regulates a complete set of genes (Sec23/24/13/31, Tango1, Sedlin, and KLHL12) essential for the enlargement of COPII vesicles to accommodate long-chain collagen for export, leading to the formation of the perinotochordal basement membrane. Thus, the most appropriate UPR transducer is activated to cope with the differing physiological ER stresses of different content types depending on developmental stage.

DOI： 10.1083/jcb.201609100

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Low-intensity pulsed ultrasound (LIPUS) treatment of cultured chondrocytes stimulates production of CCN family protein 2 (CCN2), a protein involved in the regeneration of articular cartilage: mechanism underlying this stimulation

T. Nishida, S. Kubota, E. Aoyama, N. Yamanaka, K. M. Lyons, M. Takigawa

OSTEOARTHRITIS AND CARTILAGE 25 ( 5 ) 759 - 769 2017.5

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI LTD

Objective: CCN family protein 2/connective tissue growth factor (CCN2/CTGF) promotes cartilage regeneration in experimental osteoarthritis (OA) models. However, CCN2 production is very low in articular cartilage. The aim of this study was to investigate whether or not CCN2 was promoted by cultured chondrocytes treated with low-intensity pulsed ultrasound (LIPUS) and to clarify its mechanism.
Methods: Human chondrocytic cell line (HCS)-2/8, rat primary epiphyseal and articular cartilage cells, and Ccn2-deficient chondrocytes that impaired chondrocyte differentiation, were treated with LIPUS for 20 min at 3.0 MHz frequency and 60 mW/cm(2) power. Expressions of chondrocyte differentiation marker mRNAs were examined by real-time PCR (RT-PCR) analysis from HCS-2/8 cells and Ccn2-deficient chondrocytes at 30 min and 1 h after LIPUS treatment, respectively. CCN2 production was examined by Western blotting after 5 h of LIPUS treatment. Moreover, Ca2+ influx was measured by using a Fluo-4 probe.
Results: The gene expression of chondrocyte differentiation markers and CCN2 production were increased in cultured chondrocytes treated with LIPUS. In addition, Ca2+ influx and phosphorylation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) 1/2 were increased by LIPUS treatment, and the stability of TRPV4 and BKca channel mRNAs was decreased by siRNA against CCN2. Consistent with those findings, the LIPUS-induced the gene expressions of type II collagen (COL2a1) and Aggrecan (ACAN) observed in wild-type cells were not observed in the Ccn2-deficient chondrocytes.
Conclusion: These data indicate that chondrocyte differentiation represented by CCN2 production was mediated via MAPK pathways activated by LIPUS-stimulated Ca2+ influx, which in turn was supported by the induced CCN2 molecules in articular chondrocytes. (C) 2016 Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International.

DOI： 10.1016/j.joca.2016.10.003

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Assessment of CCN2 Independent Modules Regenerative Capacity on Osteoarthritis and Further Selecting the Most Suitable Among them as a Potential Therapeutic Drug Reviewed

Abdelkader Tarek, Aoyama Eriko, Nishida Takashi, Hattori Takako, Janune Danilo, Hara Emilio S, Ono Mitsuaki, Tabata Yasuhiko, Kuboki Takuo, Kubota Satoshi, Takigawa Masaharu

FASEB JOURNAL 30 2016.4

Role of CCN2 in Amino Acid Metabolism of Chondrocytes

Yurika Murase, Takako Hattori, Eriko Aoyama, Takashi Nishida, Aya Maeda-Uematsu, Harumi Kawaki, Karen M. Lyons, Akira Sasaki, Masaharu Takigawa, Satoshi Kubota

JOURNAL OF CELLULAR BIOCHEMISTRY 117 ( 4 ) 927 - 937 2016.4

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

CCN2/connective tissue growth factor (CTGF) is a multi-functional molecule that promotes harmonized development and regeneration of cartilage through its matricellular interaction with a variety of extracellular biomolecules. Thus, deficiency in CCN2 supply profoundly affects a variety of cellular activities including basic metabolism. A previous study showed that the expression of a number of ribosomal protein genes was markedly enhanced in Ccn2-null chondrocytes. Therefore, in this study, we analyzed the impact of CCN2 on amino acid and protein metabolism in chondrocytes. Comparative metabolome analysis of the amino acids in Ccn2-null and wild-type mouse chondrocytes revealed stable decreases in the cellular levels of all of the essential amino acids. Unexpectedly, uptake of such amino acids was rather enhanced in Ccn2-null chondrocytes, and the addition of exogenous CCN2 to human chondrocytic cells resulted in decreased amino acid uptake. However, as expected, amino acid consumption by protein synthesis was also accelerated in Ccn2-null chondrocytes. Furthermore, we newly found that expression of two genes encoding two glycolytic enzymes, as well as the previously reported Eno1 gene, was repressed in those cells. Considering the impaired glycolysis and retained mitochondrial membrane potential in Ccn2-null chondrocytes, these findings suggest that Ccn2 deficiency induces amino acid shortage in chondrocytes by accelerated amino acid consumption through protein synthesis and acquisition of aerobic energy. Interestingly, CCN2 was found to capture such free amino acids in vitro. Under physiological conditions, CCN2 may be regulating the levels of free amino acids in the extracellular matrix of cartilage. J. Cell. Biochem. 117: 927-937, 2016. (c) 2015 Wiley Periodicals, Inc.

DOI： 10.1002/jcb.25377

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Assessment of CCN2 Independent Modules Regenerative Capacity on Osteoarthritis and Further Selecting the Most Suitable Among them as a Potential Therapeutic Drug Reviewed

Tarek Abdelkader, Eriko Aoyama, Takashi Nishida, Takako Hattori, Danilo Janune, Emilio S. Hara, Mitsuaki Ono, Yasuhiko Tabata, Takuo Kuboki, Satoshi Kubota, Masaharu Takigawa

FASEB JOURNAL 30 2016.4

The Role of Sonic Hedgehog Signaling in Osteoclastogenesis and Jaw Bone Destruction

Tsuyoshi Shimo, Kenichi Matsumoto, Kiyofumi Takabatake, Eriko Aoyama, Yuichiro Takebe, Soichiro Ibaragi, Tatsuo Okui, Naito Kurio, Hiroyuki Takada, Kyoichi Obata, Pai Pang, Masahiro Iwamoto, Hitoshi Nagatsuka, Akira Sasaki

PLOS ONE 11 ( 3 ) 2016.3

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Sonic hedgehog (SHH) and its signaling have been identified in several human cancers, and increased levels of its expression appear to correlate with disease progression and metastasis. However, the role of SHH in bone destruction associated with oral squamous cell carcinomas is still unclear. In this study we analyzed SHH expression and the role played by SHH signaling in gingival carcinoma-induced jawbone destruction. From an analysis of surgically resected lower gingival squamous cell carcinoma mandible samples, we found that SHH was highly expressed in tumor cells that had invaded the bone matrix. On the other hand, the hedgehog receptor Patched and the signaling molecule Gli-2 were highly expressed in the osteoclasts and the progenitor cells. SHH stimulated osteoclast formation and pit formation in the presence of the receptor activator for nuclear factor-kappa B ligand (RANKL) in CD11b(+) mouse bone marrow cells. SHH upregulated phosphorylation of ERK1/2 and p38 MAPK, NFATc1, tartrate-resistant acid phosphatase (TRAP), and Cathepsin K expression in RAW264.7 cells. Our results suggest that tumor-derived SHH stimulated the osteoclast formation and bone resorption in the tumor jawbone microenvironment.

DOI： 10.1371/journal.pone.0151731

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Evaluation of Molecular Interaction between CCN2 Protein and Its Binding Partners by Surface Plasmon Resonance (SPR).

Aoyama E, Takigawa M

Methods Mol Biol. 1489 169 - 176 2016

Involvement of multiple CCN family members in platelets that support regeneration of joint tissues

Chikako Hara, Satoshi Kubota, Takashi Nishida, Miki Hiasa, Takako Hattori, Eriko Aoyama, Yoshinori Moriyama, Hiroshi Kamioka, Masaharu Takigawa

MODERN RHEUMATOLOGY 26 ( 6 ) 940 - 949 2016

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Objectives: Platelet-rich plasma (PRP) has been widely used to enhance the regeneration of damaged joint tissues, such as osteoarthritic and rheumatoid arthritic cartilage. The aim of this study is to clarify the involvement of all of the CCN family proteins that are crucially associated with joint tissue regeneration.
Methods: Cyr61-CTGF-NOV (CCN) family proteins in human platelets and megakaryocytic cells were comprehensively analyzed by Western blotting analysis. Production of CCN family proteins in megakaryocytes in vivo was confirmed by immunofluorescence analysis of mouse bone marrow cells. Effects of CCN family proteins found in platelets on chondrocytes were evaluated by using human chondrocytic HCS-2/8 cells.
Results: Inclusion of CCN2, a mesenchymal tissue regenerator, was confirmed. Of note, CCN3, which counteracts CCN2, was newly found to be encapsulated in platelets. Interestingly, these two family members were not detectable in megakaryocytic cells, but their external origins were suggested. Furthermore, we found for the first time CCN5 and CCN1 that inhibits ADAMTS4 in both platelets and megakaryocytes. Finally, application of a CCN family cocktail mimicking platelets onto HCS-2/8 cells enhanced their chondrocytic phenotype.
Conclusions: Multiple inclusion of CCN1, 2 and 3 in platelets was clarified, which supports the harmonized regenerative potential of PRP in joint therapeutics.

DOI： 10.3109/14397595.2016.1155255

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CCN4/WISP-1 positively regulates chondrogenesis by controlling TGF-beta 3 function

Yoshioka, Yuya, Ono, Mitsuaki, Maeda, Azusa, Kilts, Tina M., Hara, Emilio Satoshi, Khattab, Hany, Ueda, Junji, Aoyama, Eriko, Oohashi, Toshitaka, Takigawa, Masaharu, Young, Marian F., Kuboki, Takuo

Bone 83 162 - 170 2016

Production of recombinant CCN2 protein in Escherichia coli

Eriko Aoyama, Takako Hattori, Satoshi Kubota, Masaharu Takigawa

Methods in Molecular Biology 1489 77 - 84 2016

Publishing type：Part of collection (book)

Recombinant proteins are important tools for understanding molecular functions in vitro. Recent progress in the generation of recombinant proteins is amazing. However, when we plan to produce them, we should choose the best method according to the nature and the use of the target recombinant protein. Degradation and mis-folding are major problems in producing active recombinant CCN2. The method shown in this chapter describes the appropriate conditions under which we can produce CCN2 and its truncated fragments in Escherichia coli.

DOI： 10.1007/978-1-4939-6430-7_8

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マウス頭蓋冠におけるリポポリサッカリドによる骨破壊とグルタチオンの効果

藤田洋史, 大野充昭, 青山絵理子, 荻野哲也, 近藤洋一, 大内淑代

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集 88回・38回 [1LBA049] - [1LBA049] 2015.12

Physical interaction of CCN2 with diverse growth factors involved in chondrocyte differentiation during endochondral ossification

Hany Mohamed Khattab, Eriko Aoyama, Satoshi Kubota, Masaharu Takigawa

JOURNAL OF CELL COMMUNICATION AND SIGNALING 9 ( 3 ) 247 - 254 2015.9

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

CCN family member 2 (CCN2) has been shown to promote the proliferation and differentiation of chondrocytes, osteoblasts, osteoclasts, and vascular endothelial cells. In addition, a number of growth factors and cytokines are known to work in harmony to promote the process of chondrogenesis and chondrocyte differentiation toward endochondral ossification. Earlier we showed that CCN2 physically interacts with some of them, suggesting that multiple effects of CCN2 on various differentiation stages of chondrocytes may be attributed to its interaction with these growth factors and cytokines. However, little is known about the functional interaction occurring between CCN2 and other growth factors and cytokines in promoting chondrocyte proliferation and differentiation. In this study we sought to shed light on the binding affinities between CCN2 and other essential growth factors and cytokines known to be regulators of chondrocyte differentiation. Using the surface plasmon resonance assay, we analyzed the dissociation constant between CCN2 and each of the following: TGF-beta 1, TGF-beta 3, IGF-I, IGF-II, PDGF-BB, GDF5, PTHrP, and VEGF. We found a strong association between CCN2 and VEGF, as well as a relatively high association with TGF-beta 1, TGF-beta 3, PDGF-BB, and GDF-5. However, the sensorgrams obtained for possible interaction between CCN2 and IGF-I, IGF-II or PTHrP showed no response. This study underlines the correlation between CCN2 and certain other growth factors and cytokines and suggests the possible participation of such interaction in the process of chondrogenesis and chondrocyte differentiation toward endochondral ossification.

DOI： 10.1007/s12079-015-0290-x

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破骨細胞分化における新規アクチン骨格制御因子としてのDCL-1/CD302の役割とCCN2との関連

青山絵理子, 星島光博, 服部高子, 久保田聡, 滝川正春

Journal of Oral Biosciences Supplement 2015 230 - 230 2015.9

CCN2 enhances RANKL-induced osteoclast differentiation via direct binding to RANK and OPG

Eriko Aoyama, Satoshi Kubota, Hany Mohamed Khattab, Takashi Nishida, Masaharu Takigawa

BONE 73 242 - 248 2015.4

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

CCN family protein 2/connective tissue growth factor (CCN2/CTGF) is a multi-potent factor for mesenchymal cells such as chondrocytes, osteoblasts, osteoclasts, and endothelial cells. CCN2 is also known as a modulator of other cytokines and receptors via direct molecular interactions with them. We screened additional factors binding to CCN2 and found receptor activator of NF-kappa B (RANK) as one of them. RANK is also known as TNF-related activation-induced cytokine (TRANCE) receptor, and its signaling plays a critical role in osteoclastogenesis. Notable affinity between CCN2 and RANK was confirmed by using surface plasmon resonance (SPR) analysis. In fact, CCN2 enhanced the RANK-mediated signaling, such as occurs in NF-kappa B, p38 and JNK pathways, in pre-osteoclastic RAW264.7 cells; whereas CCN2 had no influence on RANK RANK ligand (RANKL) binding. Moreover, CCN2 also significantly bound to osteoprotegerin (OPG), which is a decoy receptor of RANKL. Of note, OPG markedly inhibited the binding between CCN2 and RANK; and CCN2 canceled the inhibitory effect of OPG on osteoclast differentiation. These findings suggest CCN2 as a candidate of the fourth factor in the RANK/RANKL/OPG system for osteodastogenesis, which regulates OPG and RANK via direct interaction. (C) 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bone.2014.12.058

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CCN family protein 2 (CCN2) promotes the early differentiation, but inhibits the terminal differentiation of skeletal myoblasts

Takashi Nishida, Satoshi Kubota, Eriko Aoyama, Danilo Janune, Karen M. Lyons, Masaharu Takigawa

JOURNAL OF BIOCHEMISTRY 157 ( 2 ) 91 - 100 2015.2

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Many studies have reported that CCN family protein 2 (also known as connective tissue growth factor) induces fibrotic response in skeletal muscle, thus emphasizing the pathological role of CCN2 in muscle tissues. However, the physiological role of CCN2 in myogenesis is still unknown. This study clarified the CCN2 functions during myogenesis. Recombinant CCN2 (rCCN2) promoted proliferation and MyoD production in C2C12 cells and primary myoblasts, but inhibited myogenin production. In accordance with these findings, the gene expression levels of myosin heavy chain, which is a marker of terminally differentiated myoblasts and desmin, which is the main intermediate filament protein of muscle cells, were decreased by rCCN2 treatment. In vivo analyses with Ccn2-deficient skeletal muscle revealed decreased proliferating cell nuclear antigen (PCNA)/MyoD double positive cells and muscle hypoplasia. Consistent with this finding, myogenic marker genes and myotube formation were repressed in Ccn2-deficient myoblasts. The protein production of CCN2 was increased in C2C12 myoblasts treated with tumor necrosis factor-alpha, which is a pro-inflammatory cytokine, suggesting its role in muscle regeneration after inflammation. These findings indicate that CCN2 promotes proliferation and early differentiation but inhibits the terminal differentiation of myoblasts, thus suggesting that CCN2 plays a physiological role in myogenesis.

DOI： 10.1093/jb/mvu056

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新たなCCN2結合因子DCL-1の破骨細胞分化における役割

青山絵理子, 星島光博, 服部高子, 久保田聡, 滝川正春

Journal of Oral Biosciences Supplement 2014 105 - 105 2014.9

Direct interaction between CCN family protein 2 and fibroblast growth factor 1

Tarek Abd El Kader, Satoshi Kubota, Ken Anno, Saho Tanaka, Takashi Nishida, Takayuki Furumatsu, Eriko Aoyama, Takuo Kuboki, Masaharu Takigawa

JOURNAL OF CELL COMMUNICATION AND SIGNALING 8 ( 2 ) 157 - 163 2014.6

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

In an attempt to find out a new molecular counterpart of CCN family protein 2 (CCN2), a matricellular protein with multiple functions, we performed an interactome analysis and found fibroblast growth factor (FGF) -1 as one of the candidates. Solid-phase binding assay indicated specific binding between CCN2 and FGF-1. This binding was also confirmed by surface plasmon resonance (SPR) analysis that revealed a dissociation constant (Kd) of 3.98 nM indicating strong molecular interaction between the two. RNA analysis suggested that both FGF-1 and CCN2 could be produced by chondrocytes and thus their interaction in the cartilage is possible. These findings for the first time indicate the direct interaction of CCN2 and FGF-1 and suggest the co-presence of these molecules in the cartilage microenvironment. CCN2 is a well-known promoter of cartilage development and regeneration, whereas the physiological and pathological role of FGF-1 in cartilage mostly remains unclear. Biological role of FGF-1 itself in cartilage is also suspected.

DOI： 10.1007/s12079-014-0232-z

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