Protoporphyrin IX photodynamic therapy for synovitis

OBJECTIVE: To determine the conditions for synovial accumulation of protoporphyrin IX (PpIX) and photodynamic therapy (PDT)-induced synovial cytotoxicity in vitro and in vivo. METHODS: Synovial tissues were obtained from mice with antigen-induced arthritis (AIA) and incubated with different concentrations of 5-aminolevulinic acid hexyl ester (h-ALA), a PpIX precursor. Following photoexcitation, cell death in synovial tissues was evaluated by Sytox green fluorescence. PDT was performed after intraarticular injection of h-ALA into the knee joints of mice with AIA, and its effect on joint inflammation was assessed by technetium scintigraphy and histology. Synovial biopsy samples were obtained from patients with osteoarthritis (OA; n = 9) and rheumatoid arthritis (RA; n = 7) and studied for PDT-induced cytotoxicity in vitro. RESULTS: Conversion of h-ALA to PpIX was observed in inflamed synovium in mice and humans. Cytotoxicity was confirmed by Sytox green staining in samples subjected to PDT. In the AIA model, injection of affected knees with h-ALA prior to PDT led to a statistically significant reduction of joint damage in the irradiated joints. The preferential transformation of h-ALA to PpIX in inflammatory tissues was confirmed in human synovial biopsy tissues, where RA samples showed higher tissue concentrations of PpIX following incubation with h-ALA than did OA samples. Fluorescence microscopy showed that PpIX was localized to the synovial lining layer, endothelial cells, and macrophages and induced cell death after PDT. CONCLUSION: Our findings suggest that PDT based on the accumulation of PpIX in the synovial membrane may be a rational basis for photodynamic synovectomy in arthritic diseases

P2 Purinergic Receptors on Osteoblasts and Osteoclasts: Potential Targets for Drug Development

Extracellular nucleotides like ATP bind to cell surface receptors (P2 purinergic receptors) in many tissues. P2X receptor subtypes are intrinsic ion channels that mediate depolarization and influx of Ca2+, whereas the P2Y receptor subtypes couple through G proteins to activation of phospholipase Cβ and mobilization of intracellular Ca2+. In nonskeletal tissues, extracellular ATP functions in neurotransmission, stimulation of secretion, regulation of cell proliferation, and induction of apoptosis. Multiple subtypes of P2 purinergic receptors are expressed in bone. P2Y purinergic receptors have been identified in osteoblasts and osteoclasts, and P2X purinergic receptors in osteoclasts. Bone cells exhibit a number of functional responses when exposed to extracellular nucleotides. These include enhancement of osteoblast responses to parathyroid hormone and stimulation of osteoclast formation and resorptive activity. Nucleotides accumulate at sites of inflammation and tissue injury, and therefore may serve as paracrine regulators of bone cell function in diseases such as rheumatoid arthritis and periodontitis. In addition, autocrine/paracrine signaling via release of nucleotides may underlie the physiological responses of skeletal tissues to mechanical stimuli. This article reviews work from our laboratories and others on the identity of purinergic receptor subtypes in osteoblasts and osteoclasts, their associated signal transduction mechanisms, and their roles in regulating bone cell function. We discuss the potential of P2 purinergic receptors as targets for the development of anabolic and antiresorptive drugs aimed at the treatment of osteoporosis and other bone disorders

A UK Consensus Group on management of glucocorticoid-induced osteoporosis: an update.

In the UK, over 250 000 patients take continuous oral glucocorticoids (GCs), yet no more than 14% receive any therapy to prevent bone loss, a major complication of GC treatment. Bone loss is rapid, particularly in the first year, and fracture risk may double. This review, based wherever possible on clinical evidence, aims to provide easy-to-use guidance with wide applicability. A treatment algorithm is presented for adults receiving GC doses of 7.5 mg day(-1) or more for 6 months or more. General measures, e.g. alternative GCs and routes of administration, and therapeutic interventions, e.g. cyclical etidronate and hormone replacement, are recommended