ORIGINAL ARTICLE Involvement of soluble receptor activator of nuclear factor-jB ligand (sRANKL) in collagenase-induced murine osteoarthritis and human osteoarthritis Petya Dimitrova • Antoaneta Toncheva • Valeriya Gyurkovska • Nina Ivanovska Received: 14 June 2010 / Accepted: 30 December 2010 / Published online: 3 February 2011 Ó Springer-Verlag 2011 Abstract Joint destruction and excessive bone formation are associated with high expression of soluble receptor activator of nuclear factor-jB ligand (sRANKL). This study was undertaken to investigate the role of sRANKL in col- lagenase-induced osteoarthritis (CIOA) in mice and in patients with osteoarthritis (OA). The initial phase of CIOA was associated with severe proteoglycan depletion, decreased collagen density, and up-regulation of bone mor- phogenetic protein (BMP)-2. At the late stage of CIOA, bone remodeling was related with increased BMP2 and RANKL expression in the joints, high sRANKL, and decreased number of activated neutrophils in synovium. CIOA mice showed elevated plasma level of sRANKL but low RANKL expression on blood neutrophils. The percentage of RANKL-positive blood neutrophils was higher in patients with OA than in healthy individuals. Our data indicate that increased local and systemic levels of soluble RANKL might be indicative for OA disorders in mouse and human. Keywords Osteoarthritis Á Collagenase-induced osteoarthritis Á Neutrophils Á sRANKL Introduction Osteoarthritis (OA) is a disease of the whole joint charac- terized with early and progressive cartilage damage and changes in underlying subchondral bone [1]. The uncoor- dinated bone remodeling cycle in OA results from the impaired balance between bone resorption mediated by mature osteoclasts and bone formation mediated by osteo- blasts. The receptor activator of nuclear factor-jB ligand (RANKL) and its receptor RANK are actively involved in osteoclast formation [2]. RANKL is expressed by immature osteoblasts and binds to RANK on osteoclasts, initiating the recruitment of osteoclast precursors in bone marrow and promoting their differentiation. RANK interacts intracellu- larly with TNF receptor-associated factor 6 (TRAF6), which triggers downstream signaling through NF-jB, p38 kinase, and c-Jun N-terminal kinase [3]. Studies in mice deficient of RANK [4], TRAF6 [5], or NF-jB[6] showed severe oste- opetrosis, indicating the important role of these molecules for osteoclast differentiation. Several cytokines promote RANKL-induced osteoclast maturation and activity, including macrophage colony-stimulating factor, TNF-a, IL-1, IL-6, IL-15, and IL-17 [7, 8]. The action of RANKL is blocked by the soluble decoy receptor of RANKL named osteoprotegerin (OPG). OPG is secreted by osteoblasts and stromal cells and is expressed by macrophages in synovial lining layer. Now, it is assumed that bone resorption is dependent on the balance between RANKL, RANK, and OPG levels [9, 10]. The inhibition of RANKL by a highly specific antibody represents a new promising strategy for the treatment of bone diseases. Such approach has been suc- cessfully used to prevent bone destruction in serum transfer model [11], in TNF-a-induced model [12], and in autoim- mune type II collagen-induced arthritis [13]. Recently, efforts to introduce human antibody with specificity for RANKL (denosumab) in clinical practice have been also made [14]. The results of these trials have shown significant reduction of cartilage erosion and suggest therapeutic potential of RANKL inhibition for prevention of bone loss. P. Dimitrova Á V. Gyurkovska Á N. Ivanovska (&) Department of Immunology, Institute of Microbiology, Sofia, Bulgaria e-mail: nina@microbio.bas.bg A. Toncheva Clinic of Internal Diseases, National Transport Hospital, Sofia, Bulgaria 123 Rheumatol Int (2012) 32:1317–1325 DOI 10.1007/s00296-010-1723-8