Inflammation and Bone Metabolism in Rheumatoid Arthritis: Molecular Mechanisms of Joint Destruction and Pharmacological Treatments.

Rheumatoid arthritis (RA) is an inflammatory disease characterized by a variety of symptoms and pathologies often presenting with polyarthritis. The primary symptom in the initial stage is joint swelling due to synovitis. With disease progression, cartilage and bone are affected to cause joint deformities. Advanced osteoarticular destruction and deformation can cause irreversible physical disabilities. Physical disabilities not only deteriorate patients' quality of life but also have substantial medical economic effects on society. Therefore, prevention of the progression of osteoarticular destruction and deformation is an important task. Recent studies have progressively improved our understanding of the molecular mechanism by which synovitis caused by immune disorders results in activation of osteoclasts; activated osteoclasts in turn cause bone destruction and para-articular osteoporosis. In this paper, we review the mechanisms of bone metabolism under physiological and RA conditions, and we describe the effects of therapeutic intervention against RA on bone.

Downregulation of CD24 suppresses bone metastasis of lung cancer.

Suppression of bone metastasis can improve patient quality of life. Current drugs for bone metastasis have been shown to prolong progression-free survival but not overall survival; therefore, other potential therapeutic targets for bone metastasis should be investigated. Cell-surface antigens, such as CD24, have been recently shown to be involved in the metastasis of various cancers. However, whether CD24 plays a role in bone metastasis of lung cancer remains unknown. To observe metastasis of lung cancer cells by imaging technology, we introduced a near-infrared fluorescent protein, iRFP720, into a bone-seeking subclone established from lung cancer cells, HARA-B4 cells. The anchorage-independent growth of these cells was then evaluated by colony formation assays. We also compared cancer cell tropism to bone tissue with HARA-B4 cells in the presence or absence of CD24 by cell adhesion assays. To clarify the role of CD24 in bone metastasis, we intracardially injected CD24-knockdown HARA-B4 cells into mice and monitored metastasis through detection of iRFP720 using an in vivo imaging system. CD24-knockdown HARA-B4 cells in vitro showed reduced anchorage-independent growth and cancer cell tropism to bone. Bone metastasis was diminished in mice inoculated with CD24-knockdown HARA-B4 cells, which was rescued by add-back of CD24 in cells. Our findings indicate that iRFP720 is effective for in vivo imaging analysis of bone metastasis and that downregulation of CD24 suppresses bone metastasis of lung cancer cells. These findings collectively indicate that CD24 may be considered a promising new therapeutic candidate for the prevention of bone metastasis of lung cancer.

Effects of 18-month treatment with bazedoxifene on enzymatic immature and mature cross-links and non-enzymatic advanced glycation end products, mineralization, and trabecular microarchitecture of vertebra in ovariectomized monkeys.

Bazedoxifene (BZA) is used for the treatment of post-menopausal osteoporosis. To elucidate changes in collagen, mineralization, and structural properties and their relationship to bone strength after treatment with BZA in ovariectomized (OVX) monkeys, the levels of collagen and enzymatic immature, mature, and non-enzymatic cross-links were simultaneously examined, as well as trabecular architecture and mineralization of vertebrae. Adult female cynomolgus monkeys were divided into 4 groups (n=18 each) as follows: Sham group, OVX group, and OVX monkeys given either 0.2 or 0.5mg/kg BZA for 18 months. Collagen concentration, enzymatic and non-enzymatic pentosidine cross-links, whole fluorescent advanced glycation end products (AGEs), trabecular architecture, mineralization, and cancellous bone strength of vertebrae were analyzed. The levels of enzymatic immature and mature cross-links, bone volume (BV/TV), and trabecular thickness (Tb.Th) in BZA-treated groups were significantly higher than those in the OVX control group. In contrast, the trabecular bone pattern factor (TBPf), the structure model index (SMI), the enzymatic cross-link ratio, and the levels of pentosidine and whole AGEs in BZA-treated groups were significantly lower than those in the OVX control group. Stepwise logistic regression analysis revealed that BV/TV, Tb.Th, TbPf, and pentosidine or whole AGEs independently affected ultimate load (model R(2)=0.748, p<0.001) and breaking energy (model R(2)=0.702). Stiffness was affected by Tb.Th, enzymatic immature cross-link levels and their ratio (model R(2)=0.400). Treatment with BZA prevented OVX-induced deterioration in the total levels of immature enzymatic cross-links and AGEs accumulation and structural properties such as BV/TV, Tb.Th, and TbPf, which contribute significantly to vertebral cancellous bone strength.