A novel aza-anthrapyrazole blocks the progression of experimental autoimmune encephalomyelitis after the priming of autoimmunity.

Mitoxantrone is one of the few FDA-approved drugs available to treat rapidly progressing forms of multiple sclerosis; however, its utilization is compromised by a cardiotoxic potential and the risk of mitoxantrone-induced leukemia. BBR3378, a novel aza-anthrapyrazole, is structurally similar to mitoxantrone, but lacks the ring hydroxyls that may contribute to cardiotoxicity. Here, we investigated the therapeutic activity of BBR3378 in a C57BL/6 mouse model of multiple sclerosis. Mice given BBR3378, before or after the priming and expansion of MOG-specific responses, were protected from ascending paralysis. Strikingly, two doses of BBR3378 given a week after EAE induction were sufficient to provide significant protection from clinical symptoms and reduce MOG-specific proinflammatory T cell cytokine production, and serum IgG responses. Furthermore, while mitoxantrone is associated with persistent lymphopenia and cardiotoxicity, no such outcomes were detected in BBR3378-treated mice. Our findings show that BBR3378 can ameliorate encephalitogenic mechanisms in EAE and antagonize underlying autoimmune mechanisms.

The role of inhibition by phosphocitrate and its analogue in chondrocyte differentiation and subchondral bone advance in Hartley guinea pigs.

Phosphocitrate (PC) and its analogue, PC-ß ethyl ester, inhibit articular cartilage degeneration in Hartley guinea pigs. However, the underlying molecular mechanisms remain unclear. The present study aimed to investigate the hypothesis that PC exerted its disease-modifying effect on osteoarthritis (OA), in part, by inhibiting a molecular program similar to that in the endochondral pathway of ossification. The results demonstrated that severe proteoglycan loss occurred in the superficial and middle zones, as well as in the calcified zone of articular cartilage in the Hartley guinea pigs. Subchondral bone advance was greater in the control Hartley guinea pigs compared with PC- or PC analogue-treated guinea pigs. Resorption of cartilage bars or islands and vascular invasion in the growth plate were also greater in the control guinea pigs compared with the PC- or PC analogue-treated guinea pigs. The levels of matrix metalloproteinase-13 and type X collagen within the articular cartilage and growth plate were significantly increased in the control guinea pigs compared with PC-treated guinea pigs (P<0.05). These results indicated that articular chondrocytes in Hartley guinea pigs exhibited a hypertrophic phenotype and recapitulated a developmental molecular program similar to the endochondral pathway of ossification. Activation of this molecular program resulted in resorption of calcified articular cartilage and subchondral bone advance. This suggests that PC and PC analogues exerted their OA disease-modifying activity, in part, by inhibiting this molecular program.

Comparison of Meniscal Cell-Mediated and Chondrocyte-Mediated Calcification.

BACKGROUND: Chondrocytes have been traditionally thought to be responsible for calcium crystal deposits within osteoarthritic knees. Increasing recent experimental evidence suggests that menisci may also play a role. However, the calcifying potential of chondrocytes and meniscal cells derived from same OA patients, and the genes associated with meniscal calcification have never been fully examined. OBJECTIVE: Examine and compare the calcifying potential of articular chondrocytes and meniscal cells derived from same OA patients and identify the calcium crystal type(s) and selected gene expression in OA menisci. METHODS: Chondrocytes and meniscal cells were isolated from articular cartilage and menisci of OA patients undergoing total knee arthroplasty. Chondrocyte- and meniscal cell-mediated calcification was examined using both monolayer and micromass culture-based assays. Crustal types were examined with histological staining. Levels of Type X Collagen, MMP-13, and ANKH in OA menisci were examined using immunohistochemistry. RESULTS: Primary human OA meniscal cells produced calcified deposits at a similar rate compared to OA chondrocytes in-vitro. Histological examinations indicate that both BCP crystals and CPPD crystals are present in the meniscal tissue. Type X collagen, MMP-13, and ANKH were found in human OA menisci and their levels increased with OA severity. In addition, type X collagen was co-localized with calcium crystals. CONCLUSION: These findings suggest that OA meniscal cells have a similar calcifying potential as OA chondrocytes, supporting a pathogenic role of OA menisci in OA.

Apigenin inhibits COX-2, PGE2, and EP1 and also initiates terminal differentiation in the epidermis of tumor bearing mice.

Non-melanoma skin cancer (NMSC) is the most prevalent cancer in the United States. NMSC overexpresses cyclooxygenase-2 (COX-2). COX-2 synthesizes prostaglandins such as PGE2 which promote proliferation and tumorigenesis by engaging G-protein-coupled prostaglandin E receptors (EP). Apigenin is a bioflavonoid that blocks mouse skin tumorigenesis induced by the chemical carcinogens, 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). However, the effect of apigenin on the COX-2 pathway has not been examined in the DMBA/TPA skin tumor model. In the present study, apigenin decreased tumor multiplicity and incidence in DMBA/TPA-treated SKH-1 mice. Analysis of the non-tumor epidermis revealed that apigenin reduced COX-2, PGE2, EP1, and EP2 synthesis and also increased terminal differentiation. In contrast, apigenin did not inhibit the COX-2 pathway or promote terminal differentiation in the tumors. Since fewer tumors developed in apigenin-treated animals which contained reduced epidermal COX-2 levels, our data suggest that apigenin may avert skin tumor development by blocking COX-2.