Up-Regulation of the Inflammatory Response by Ovariectomy in Collagen-Induced Arthritis. Effects of Tin Protoporphyrin IX Lidia Ibáñez, 1 Maria José Alcaraz, 1 Nuria Maicas, 1 David Guede, 2 José Ramón Caeiro, 3 Marije I. Koenders, 4 Wim B. van den Berg, 4 and Maria Luisa Ferrándiz 1,5 Abstract—We have studied the influence of ovariectomy on the inflammatory response and bone metabolism on CIA as a model of postmenopausal arthritis as well as the effects of tin protoporp- hyrin IX (SnPP), a heme oxygenase inhibitor. Ovariectomy in non-arthritic mice produced increased serum PGD 2 levels and up-regulated the expression of COX-2, h-PGDS, l-PGDS, and HO-1 in the joints. In CIA, ovariectomy potentiated the inflammatory response with higher levels of serum IL-6 and MMP-3, local PGD 2 and MMP-3 as well as trabecular bone erosion. In OVX-CIA, SnPP decreased the serum levels of IL-6, MMP-3, and PGD 2 ; down-regulated TNFα, COX-2, hPGDS, PGD 2 , PGE 2 , and MMP-3 in joint tissues; and also decreased focal bone loss in the inflamed joint. Ovariectomy up-regulates inflammatory mediators in non-arthritic and in arthritic animals. In the OVX-CIA model, SnPP exerts anti-inflammatory effects which are not associated with the preve- ntion of systemic bone loss. KEY WORDS: ovariectomy; collagen-induced arthritis; bone metabolism; prostaglandin D 2 ; tin protoporphyrin IX. INTRODUCTION Rheumatoid arthritis (RA) is an autoimmune dis- ease characterized by persistent synovial inflammation as well as articular cartilage and bone destruction. In particular, focal bone erosion, periarticular osteopenia adjacent to inflamed joints, and generalized osteoporosis have been described, resulting in an important disability [1]. The incidence of RA and joint destruction is greater in women compared with men and can be related to menopause [2, 3]. A decrease in estrogen levels following menopause can have a profound impact on the development and progression of autoimmune dis- eases. It is known that hormone replacement therapy or estrogen administration exerts inhibitory effects on the inflammatory and bone changes of RA, but they are associated with important side effects [4, 5]. The mouse collagen-induced arthritis (CIA) has been extensively used as a model of RA. Recently, induction of arthritis by type II collagen in ovariectom- ized DBA/1 mice has been proposed as a model of postmenopausal RA where the loss of estrogen and inflammation contribute equally to osteoporosis [6]. Heme oxygenase-1 (HO-1) is induced in many cells by oxidative stress and a wide range of stimuli. Induction of this protein may exert antioxidant effects ABBREVIATIONS: AP, Alkaline phosphatase; CII, Type II collagen; CIA, Collagen-induced arthritis; COMP, Cartilage oligomeric matrix protein; COX-2, Cyclooxygenase-2; ELISA, Enzyme-linked immuno- assay; HO-1, Heme oxygenase-1; IL, Interleukin; h-PGDS, Hemato- poietic-prostaglandin D synthase; l-PGDS, Lipocalin-prostaglandin D synthase; MMP, Matrix metalloproteinase; NA, Naïve group; OVX, Ovariectomized group; OVX-CIA, Ovariectomized arthritic group; RA, Rheumatoid arthritis; RANKL, Receptor activator of nuclear factor κB ligand; SnPP, Tin protoporphyrin IX; TRAP-5b, Tartrate- resistant acid phosphatase 5b; TNFα, Tumor necrosis factor-α 1 Department of Pharmacology, University of Valencia, Av. Vicent Andres Estelles s/n, 46100, Burjasot, Valencia, Spain 2 Trabeculae S.L., 32900, San Cibrao das Viñas, Ourense, Spain 3 Santiago de Compostela University Hospital, 15706, Santiago de Compostela, Spain 4 Rheumatology Research & Advanced Therapeutics, Radboud Uni- versity Nijmegen Medical Centre, Postbus 9101, 6500 HB, Nijmegen, The Netherlands 5 To whom correspondence should be addressed at Department of Pharmacology, University of Valencia, Av. Vicent AndresEstelles s/n, 46100, Burjasot, Valencia, Spain. E-mail: luisa.ferrandiz@uv.es 0360-3997/11/0600-0585/0 # 2010 Springer Science+Business Media, LLC Inflammation, Vol. 34, No. 6, December 2011 ( # 2010) DOI: 10.1007/s10753-010-9266-4 585