Effects of antibody to receptor activator of nuclear factor κ-B ligand on inflammation and cartilage degradation in collagen antibody-induced arthritis in mice

Journal of Negative Results in Biomedicine

Ryutaro Kamijo²  Katsunori Inagaki⁵  Kazuyoshi Baba⁴  Osamu Namiki⁵  Masanori Nakamura³  Kenji Mishima¹  Hiroaki Suzuki²  Risa Uyama²  Dai Suzuki²  Junichi Tanaka¹  Kentaro Yoshimura²  Yoichi Miyamoto²  Koei Oh³  Akihiro Matsunaga⁵  Sakie Funato⁴ 

[1] Department of Oral Diagnostic Sciences, Division of Pathology, Showa University School of Dentistry, Tokyo, Japan;Department of Biochemistry, Showa University School of Dentistry, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8555, Japan;Department of Orthopaedic Surgery, Showa University Northern Yokohama Hospital, Yokohama, Japan;Department of Prosthodontics, Showa University School of Dentistry, Tokyo, Japan;Department of Orthopaedic Surgery, Showa University School of Medicine, Tokyo, Japan

关键词: Articular cartilage;    Inflammation;    Antibody;    RANKL;    Collagen antibody-induced arthritis;    Rheumatoid arthritis;   

Others  :  1133138
DOI  :  10.1186/s12952-014-0018-0

 received in 2014-08-30, accepted in 2014-11-20,  发布年份 2014

【 摘 要 】

Background

Rheumatoid arthritis (RA) is an inflammatory disease that leads to destruction of both articular cartilage and bone tissues. In rheumatic joints, synoviocytes and T-lymphocytes as well as bone cells produce the receptor activator of nuclear factor κ-B (RANK) ligand (RANKL), which binds to RANK on the surface of osteoclasts and their precursor cells to induce differentiation and activation of osteoclasts. Hence, inhibition of RANKL may be a promising approach to suppress osteolysis in RA. On the other hand, RANKL production by lymphocytes indicates the possibility that its inhibition would be effective to suppress inflammation in RA. In addition, it has been reported that cathepsin K, a predominant cysteine protease in osteoclasts, is involved in cartilage destruction in RA model mice. Here, we evaluated the effects of an anti-RANKL antibody on inflammation in footpads and degradation of articular cartilage in RA model mice.

Results

We induced arthritis in mice by injection of anti-type II collagen antibodies and lipopolysaccharide (LPS). Inhibition of RANKL by an anti-RANKL antibody (OYC1, Oriental Yeast, Tokyo, Japan) was confirmed by increased bone volume in the metaphysis of tibias. Swelling in either limb until day 14 was seen in 5 of 6 mice injected with anti-collagen antibodies and LPS without treatment with OYC1, while that was seen in 4 of 5 mice treated with OYC1. The average arthritis scores on day 14 in those groups were 2.17 and 3.00, respectively, indicating that OYC1 did not ameliorate inflammation in the limbs. Histological analyses indicated that OYC1 does not protect articular cartilage from destruction in mice with arthritis.

Conclusions

Our present study failed to show the effectiveness of an anti-RANKL antibody to ameliorate inflammation in the limbs or protect articular cartilage from degradation in a collagen antibody-induced arthritis mouse model.

【 授权许可】

   
2014 Funato et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Ospelt C, Neidhart M, Gay RE, Gay S: Synovial activation in rheumatoid arthritis. Front Biosci 2004, 9:2323-2334.
• [2]Tanaka S, Nakamura K, Takahashi N, Suda T: Role of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL-RANK signaling system. Immunol Rev 2005, 208:30-49.
• [3]Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Fung JQ, Bonewald LF, Kodama T, Wutz A, Wagner EF, Penninger JM, Takayanagi H: Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 2011, 17:1231-1234.
• [4]Goldring SR: Pathogenesis of bone and cartilage destruction in rheumatoid arthritis. Rheumatology 2003, 42(Suppl):ii1-ii16.
• [5]Takayanagi H: New developments in osteoimmunology. Nat Rev Rheumatol 2012, 8:684-689.
• [6]Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutiluk S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christansen C: Freedom Trial: Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009, 361:756-765.
• [7]Yee AJ, Raje NS: Denosumab, a RANK kigand inhibitor, for the management of bone loss in cancer patients. Clin Interv Aging 2012, 7:331-338.
• [8]Cohen SB, Dore RK, Lane NE, Ory PA, Peterfy CG, Sharp JT, van der Heijde D, Zhou L, Tsuji W, Newmark R: Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis. Arthritis Rheumat 2008, 58:1299-1309.
• [9]Sinningen K, Tsourdi E, Rauner M, Rachner TD, Hamann C, Hofbauer LC: Skeletal and extraskeletal actions of denosumab. Endocrine 2012, 42:52-62.
• [10]Li Z, Hou W-S, Brömme D: Collagenolytic activity of cathepsin K is specifically modulated by cartilage-resident chondroitin sulfates. Biochemistry 2000, 39:529-536.
• [11]Hou W-S, Li W, Keyszer G, Weber E, Levy R, Klein MJ, Gravallese EM, Goldring SR, Brömme D: Comparison of cathepsin K and S expression within the rheumatoid and osteoarthritic synovium. Arthritis Rheum 2002, 46:663-674.
• [12]Svelander L, Erlandsson-Harris H, Astner L, Grabowska U, Klareskog L, Lindstrom E, Hewitt E: Inhibition of cathepsin K reduces bone erosion, cartilage degradation and inflammation evoked by collagen-induced arthritis in mice. Eur J Pharmacol 2009, 613:155-162.
• [13]Furuya Y, Mori K, Ninomiya T, Tomimori Y, Yanaka S, Takahashi N, Udagawa N, Uchida K, Yasuda H: Increased bone mass in mice after single injection of anti-receptor activator of nuclear factor-kB ligand-neutralizing antibody: evidence for bone anabolic effect of parathyroid hormone in mice with few osteoclasts. J Biol Chem 2011, 286:37023-37031.
• [14]Leibbrandt A, Penninger JM: RANK/RANKL: regulators of immune responses and bone physiology. Ann NY Acad Sci 2008, 1143:123-150.
• [15]Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ: Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998, 93:165-176.
• [16]Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T: Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A 1998, 95:3597-3602.
• [17]Romas E, Sims NA, Hards DK, Lindsay M, Quinn JWM, Ryan PFJ, Dunstan CR, Martin J, Gillespie MT: Osteoprtegerin reduces osteoclast numbers and prevents bone erosion in collagen-induced arthritis. Am J Pathol 2002, 161:1419-1427.
• [18]Redlich K, Görtz B, Hayer S, Zwerina J, Doerr N, Kostenuik P, Bergmeister H, Kollias G, Steiner G, Snolen JS, Schett G: Repair of local bone erosions and reversal of systemic bone loss upon therapy with anti-tumor necrosis factor in combination with osteoprotegerin or parathyroid hormone in tumor necrosis factor-mediated arthritis. Am J Pathol 2004, 164:543-555.
• [19]Schett G, Middleton S, Bolon B, Stolina M, Brown H, Zhu L, Pretorius J, Zak DJ, Kostenuik P, Feige U: Additive bone-protective effects of anabolic treatment when used in conjunction with RANKL and tumor necrosis factor inhibition in two rat arthritis models. Arthritis Rheumat 2005, 52:1604-1611.
• [20]Stolina M, Schett G, Dwyer D, Vonderfecht S, Middleton S, Duryea D, Pacheco E, Van G, Bolon B, Feige U, Zack D, Kostenuil P: RANKL inhibition by osteoprotegerin prevents bone loss without affecting local or systemic inflammation parameters in two rat arthritis models: comparison with anti-TNFα or anti-IL-1 therapies. Arthritis Res Ther 2009, 11:1-15. BioMed Central Full Text