Bone remodelling and bone loss are controlled by a balance between the tumour necrosis factor family molecule osteoprotegerin ligand (OPGL) and its decoy receptor osteoprotegerin (OPG)1,2,3. In addition, OPGL regulates lymph node organogenesis, lymphocyte development and interactions between T cells and dendritic cells in the immune system3,4,5. The OPGL receptor, RANK, is expressed on chondrocytes, osteoclast precursors and mature osteoclasts4,6. OPGL expression in T cells is induced by antigen receptor engagement7, which suggests that activated T cells may influence bone metabolism through OPGL and RANK. Here we report that activated T cells can directly trigger osteoclastogenesis through OPGL. Systemic activation of T cells in vivo leads to an OPGL-mediated increase in osteoclastogenesis and bone loss. In a T-cell-dependent model of rat adjuvant arthritis characterized by severe joint inflammation, bone and cartilage destruction and crippling, blocking of OPGL through osteoprotegerin treatment at the onset of disease prevents bone and cartilage destruction but not inflammation. These results show that both systemic and local T-cell activation can lead to OPGL production and subsequent bone loss, and they provide a novel paradigm for T cells as regulators of bone physiology.

Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand

https://www.oarsijournal.com/article/S1063-4584(10)00238-4/pdf

The OARSI histopathology initiative – recommendations for histological assessments of osteoarthritis in the mouse

TNF and TNFR family proteins play important roles in the control of cell death, proliferation, autoimmunity, the function of immune cells, or the organogenesis of lymphoid organs. Recently, novel members of this large family have been identified that have critical functions in immunity and that couple lymphoid cells with other organ systems such as bone morphogenesis and mammary gland formation in pregnancy. The TNF-family molecule RANK-L (RANK-L, TRANCE, ODF) and its receptor RANK are key regulators of bone remodeling, and they are essential for the development and activation of osteoclasts. Intriguingly, RANK-L/RANK interactions also regulate T cell/dendritic cell communications, dendritic cell survival, and lymph node formation; T cell-derived RANK-L can mediate bone loss in arthritis and periodontal disease. Moreover, RANK-L and RANK are expressed in mammary gland epithelial cells, and they control the development of a lactating mammary gland during pregnancy and the propagation of mammalian species. Modulation of these systems provides us with a unique opportunity to design novel therapeutics to inhibit bone loss in arthritis, periodontal disease, and osteoporosis.

RANK-L and RANK: T Cells, Bone Loss, and Mammalian Evolution

Osteoclasts and osteoblasts dictate skeletal mass, structure, and strength via their respective roles in resorbing and forming bone Bone remodeling is a spatially coordinated lifelong process whereby old bone is removed by osteoclasts and replaced by bone-forming osteoblasts The refilling of resorption cavities is incomplete in many pathological states, which leads to a net loss of bone mass with each remodeling cycle Postmenopausal osteoporosis and other conditions are associated with an increased rate of bone remodeling, which leads to accelerated bone loss and increased risk of fracture Bone resorption is dependent on a cytokine known as RANKL (receptor activator of nuclear factor kappaB ligand), a TNF family member that is essential for osteoclast formation, activity, and survival in normal and pathological states of bone remodeling The catabolic effects of RANKL are prevented by osteoprotegerin (OPG), a TNF receptor family member that binds RANKL and thereby prevents activation of its single cognate receptor called RANK Osteoclast activity is likely to depend, at least in part, on the relative balance of RANKL and OPG Studies in numerous animal models of bone disease show that RANKL inhibition leads to marked suppression of bone resorption and increases in cortical and cancellous bone volume, density, and strength RANKL inhibitors also prevent focal bone loss that occurs in animal models of rheumatoid arthritis and bone metastasis Clinical trials are exploring the effects of denosumab, a fully human anti-RANKL antibody, on bone loss in patients with osteoporosis, bone metastasis, myeloma, and rheumatoid arthritis

/pdf/receptor-activator-of-nuclear-factor-kb-ligand-and-34qwxtybhs.pdf

Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease

The balance between IL-1 and IL-1Ra in disease.

Animal models of arthritis are used to evaluate potential antiarthritis drugs for clinical use. Therefore capacity of the model to predict efficacy in human disease is one of the most important criteria in model selection. Animal models of rheumatoid arthritis (RA) with a proven track record of predictability include rat adjuvant arthritis, rat type II collagen arthritis, mouse type II collagen arthritis, and antigen-induced arthritis in several species. Agents currently in clinical use (or trials) that are active in these models include corticosteroids, methotrexate, nonsteroidal anti-inflammatory drugs, cyclosporin A, leflunomide, interleukin-1 receptor antagonist, and soluble tumor necrosis factor receptors. For some of these agents, the models also predict that toxicities seen at higher doses for prolonged periods would preclude dosing in humans at levels that might provide disease-modifying effects. Animal models of osteoarthritis (OA) include mouse and guinea pig spontaneous OA, meniscectomy and ligament transection in guinea pigs, meniscectomy in rabbits, and meniscectomy and cruciate transection in dogs. None of these models have a proven track record of predictability in human disease because there are no agents that have been proven to provide anything other than symptomatic relief in human OA. Efficacy data and features of the various models of RA and OA are discussed with emphasis on their proven relevance to human disease.

Animal Models of Arthritis: Relevance to Human Disease

Objective
To determine the role of interleukin-1 receptor antagonist (IL-1Ra) in rat adjuvant arthritis and rat type II collagen–induced arthritis, and to compare the efficacy in rat models with that seen in human clinical trials of IL-1Ra.

Methods
Rats with developing adjuvant arthritis or established collagen-induced arthritis were treated with IL-1Ra by continuous infusion in order to determine and maintain efficacious blood levels of this IL-1 inhibitory protein in the rats for comparison with human clinical data. The effects of treatment in the rats were monitored by sequential caliper measurement of the ankle joints, determination of final paw weights, and histologic evaluation with particular emphasis on bone and cartilage lesions. The effects of IL-1Ra on joint swelling and radiographic bone damage in patients with rheumatoid arthritis (RA) in a 6-month trial were compared with the findings in rats.

Results
Dramatic differences in the profile of IL-1Ra activity were seen between the 2 groups of rats. Modest antiinflammatory effects were observed in the adjuvant arthritis rats treated with IL-1Ra. However, marked inhibition of bone resorption occurred, even at doses with which antiinflammatory activity was not seen. In contrast, IL-1Ra treatment of rats with established collagen-induced arthritis resulted in nearly complete suppression of all aspects of the disease when adequate blood levels of IL-1Ra were maintained. Treatment of RA patients with IL-1Ra (150 mg daily) resulted in modest inhibition of joint swelling and inhibition of radiographic progression of bone lesions.

Conclusion
IL-1 appears to be of major importance in mediating the bone resorption that occurs in rat adjuvant arthritis, but is less important in the pathogenesis of periarticular inflammation in this disease. In contrast, IL-1 is of major importance in mediating all aspects of disease progression in rat collagen-induced arthritis. Similar to the response in adjuvant arthritic rats, RA patients treated with IL-1Ra showed only modest antiinflammatory activity, but had evidence of inhibition of progression of bone resorption. However, a comparison of the plasma levels of IL-1Ra in humans and rats suggests that the optimal level of dosing for continuous saturation of IL-1 receptors may not have been achieved in humans, although this was achieved in the rat studies.

Efficacy of sustained blood levels of interleukin-1 receptor antagonist in animal models of arthritis: comparison of efficacy in animal models with human clinical data.

Purpose. To determine the effect of hylan fluid (HA), a model slow release vehicle on the pharmacokinetic profile and efficacy of interleukin-1 receptor antagonist (IL-lra) in rats with established type II collagen arthritis.

Tracy McAbee

Papers

Animal Models of Arthritis: Relevance to Human Disease

Efficacy of sustained blood levels of interleukin-1 receptor antagonist in animal models of arthritis: comparison of efficacy in animal models with human clinical data.

Effects of Interleukin-1 Receptor Antagonist in a Slow-Release Hylan Vehicle on Rat Type II Collagen Arthritis