Follistatin alleviates synovitis and articular cartilage degeneration induced by carrageenan

Jun Yamada¹, Kunikazu Tsuji², Kazumasa Miyatake¹, Yu Matsukura¹, Kahaer Abula¹, Makiko Inoue³, Ichiro Sekiya⁴, Takeshi Muneta⁵

Affiliations

¹ Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
² Department of Cartilage Regeneration, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan ; International Research Center for Molecular Science in Tooth and Bone Diseases (Global Center of Excellence Program), Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
³ Department of Plastic and Reconstructive Surgery, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
⁴ Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
⁵ Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan ; Department of Cartilage Regeneration, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan ; International Research Center for Molecular Science in Tooth and Bone Diseases (Global Center of Excellence Program), Tokyo Medical and Dental University, Tokyo 113-8519, Japan.

PMID: 25574420
PMCID: PMC4276300
DOI: 10.1155/2014/959271

Follistatin alleviates synovitis and articular cartilage degeneration induced by carrageenan

Jun Yamada et al. Int J Inflam. 2014.

. 2014:2014:959271.

doi: 10.1155/2014/959271. Epub 2014 Dec 9.

Authors

Jun Yamada¹, Kunikazu Tsuji², Kazumasa Miyatake¹, Yu Matsukura¹, Kahaer Abula¹, Makiko Inoue³, Ichiro Sekiya⁴, Takeshi Muneta⁵

Affiliations

¹ Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
² Department of Cartilage Regeneration, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan ; International Research Center for Molecular Science in Tooth and Bone Diseases (Global Center of Excellence Program), Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
³ Department of Plastic and Reconstructive Surgery, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
⁴ Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
⁵ Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan ; Department of Cartilage Regeneration, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan ; International Research Center for Molecular Science in Tooth and Bone Diseases (Global Center of Excellence Program), Tokyo Medical and Dental University, Tokyo 113-8519, Japan.

PMID: 25574420
PMCID: PMC4276300
DOI: 10.1155/2014/959271

Abstract

Activins are proinflammatory cytokines which belong to the TGFβ superfamily. Follistatin is an extracellular decoy receptor for activins. Since both activins and follistatin are expressed in articular cartilage, we hypothesized that activin-follistatin signaling participates in the process of joint inflammation and cartilage degeneration. To test this hypothesis, we examined the effects of follistatin in a carrageenan-induced mouse arthritis model. Synovitis induced by intra-articular injection of carrageenan was significantly alleviated by preinjection with follistatin. Macrophage infiltration into the synovial membrane was significantly reduced in the presence of follistatin. In addition, follistatin inhibited proteoglycan erosion induced by carrageenan in articular cartilage. These data indicate that activin-follistatin signaling is involved in joint inflammation and cartilage homeostasis. Our data suggest that follistatin can be a new therapeutic target for inflammation-induced articular cartilage degeneration.

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Figures

**Figure 1**
Carrageenan-induced arthritis model. (a) Experimental design of carrageenan-induced arthritis model. Twenty-eight male mice (12-week-old) were registered in this study. Mice were randomly divided into two groups: carrageenan group (CA) and carrageenan + follistatin (CA + FLT) group (n = 14/group). Histological analyses were performed at days 3 and 14. (b, c) Procedure of intra-articular injection of carrageenan. PT: patellar tendon.

**Figure 2**
Histological analyses of synovial inflammation induced by carrageenan. (a, b) H&E staining of sagittal sections of mice knee joints at day 3 (a) and day 14 (b) after carrageenan injection. Boxed areas in the left panels are magnified and presented in the right panels. CA: carrageenan group; CA + FLT: carrageenan + follistatin group; Con: control group. Magnification: left ×40, right ×100. (c) Semiquantitative analyses of synovial inflammation. The severity of synovial inflammation was evaluated according to the synovitis scoring system (*Synovitis Score* (*Blom et al., osteoarthritis and cartilage, 2004* [20])). The synovitis scores are indicated as the total of four different areas in the knee joint as denoted in upper panel. (^* P < 0.05). (d, e) Immunohistochemical analyses of macrophage infiltration into synovial membrane at day 3 (d) and at day 14 (e) after carrageenan injection. Sagittal sections of mice knee joints were stained with F4/80 antibody. Sections were counterstained with hematoxylin. Boxed areas in the left panels are magnified and presented in the right panels. CA: carrageenan group; CA + FLT: carrageenan + follistatin group; Con: control group. Magnification: left ×40, right ×100. (f) Semiquantitative analyses of the degree of F4/80-positive macrophage infiltration into synovial membrane (*F4/80 Score* (*Willis et al., JOI, 2012* [22])). The scores were indicated as the total of four different areas of the synovial membrane (superficial layer (boxed by red) and deep layer (boxed by blue) of suprapatellar or infrapatellar region) as described in the upper panel (^* P < 0.05).

**Figure 3**
Histological analyses of articular cartilage degeneration induced by carrageenan at day 3. (a) Safranin-O staining of sagittal sections of mice knee joints at day 3 after carrageenan injection. Boxed areas in the top panels are magnified and presented in the bottom panels. CA: carrageenan group; CA + FLT: carrageenan + follistatin group; Con: control group; FLT: follistatin group. Magnification: top ×40, bottom ×100. Arrowhead indicates the region where proteoglycan erosion is observed. (b) Semiquantitative analyses of articular cartilage degeneration. The degree of articular cartilage degeneration was semiquantitatively evaluated (*Modified Coles Score* (*Coles et al., Arthritis & Rheumatology, 2010*)) [19]. Histological scores of articular cartilage from femurs and tibiae were evaluated, respectively, and total scores were compared between the two groups (^* P < 0.05).

**Figure 4**
Histological analyses of articular cartilage degeneration induced by carrageenan at day 14. (a) Safranin-O staining of sagittal sections of mice knee joints at day 14 after carrageenan injection. Boxed areas in the top panels are magnified and presented in the bottom panels. CA: carrageenan group; CA + FLT: carrageenan + follistatin group; Con: control group. Magnification: top ×40, bottom ×100. (b) Semiquantitative analyses of articular cartilage degeneration. The degree of articular cartilage degeneration was semiquantitatively evaluated (*Modified Coles Score* (*Coles et al., Arthritis & Rheumatology, 2010*) [19]). Histological scores of articular cartilage from femurs and tibiae were evaluated, respectively, and total scores were compared between the two groups (^* P < 0.05).

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Follistatin alleviates synovitis and articular cartilage degeneration induced by carrageenan

Affiliations

Follistatin alleviates synovitis and articular cartilage degeneration induced by carrageenan

Authors

Affiliations

Abstract

Figures

References

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