Rheumatoid Arthritis: Penninger JM

Leibbrandt A, Penninger JM. · IMBA, Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria. · Ann N Y Acad Sci. · Pubmed #19076348 No free full text.

Abstract: Bone-related diseases, such as osteoporosis and rheumatoid arthritis, affect hundreds of millions of people worldwide and pose a tremendous burden to health care. By deepening our understanding of the molecular mechanisms of bone metabolism and bone turnover, it became possible over the past years to devise new and promising strategies for treating such diseases. In particular, three tumor necrosis factor (TNF) family molecules, the receptor activator of NF-kappaB (RANK), its ligand RANKL, and the decoy receptor of RANKL, osteoprotegerin (OPG), have attracted the attention of scientists and pharmaceutical companies alike. Genetic experiments revolving around these molecules established their pivotal role as central regulators of osteoclast development and osteoclast function. RANK-RANKL signaling not only activates a variety of downstream signaling pathways required for osteoclast development, but crosstalk with other signaling pathways also fine-tunes bone homeostasis both in normal physiology and disease. In addition, RANKL and RANK have essential roles in lymph node formation, establishment of the thymic microenvironment, and development of a lactating mammary gland during pregnancy. Consequently, novel drugs specifically targeting RANK, RANKL, and their signaling pathways in osteoclasts are expected to revolutionize the treatment of various ailments associated with bone loss, such as arthritis, periodontal disease, cancer metastases, and osteoporosis.

Wada T, Nakashima T, Hiroshi N, Penninger JM. · Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Dr. Bohrgasse 3, A-1030 Vienna, Austria. · Trends Mol Med. · Pubmed #16356770 No free full text.

Abstract: Hundreds of millions of people worldwide are affected by bone-related diseases, such as osteoporosis and rheumatoid arthritis. Understanding the molecular mechanisms of bone metabolism is crucial for developing novel drugs for treating such diseases. In particular, genetic experiments showing that the receptor activator of NF-kappaB (RANK), its ligand RANKL, and the decoy receptor OPG are essential, central regulators of osteoclast development and osteoclast function were significant turning points in our understanding of bone diseases. RANKL-RANK signaling activates a variety of downstream signaling pathways required for osteoclast development. Moreover, molecular cross-talk between RANKL-RANK and other ligand-receptor systems fine-tunes bone homeostasis in normal physiology and disease. Designing novel drugs that target RANKL-RANK and their signaling pathways in osteoclasts could potentially revolutionize the treatment of many diseases associated with bone loss such as arthritis, tooth loss, cancer metastases or osteoporosis.

Cheng HY, Penninger JM. · IMBA, Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Dr Bohr Gasse 3-5, A-1030 Vienna, Austria. · Ann Rheum Dis. · Pubmed #15479877 links to  free full text

Abstract: The experience of acute pain serves a crucial biological purpose: it alerts a living organism to environmental dangers, inducing behavioural responses which protect the organism from further damage. In contrast, chronic pain arising from disease states and/or pathological functioning of the nervous system offers no advantage and may be debilitating to those afflicted. Despite recent advances in our understanding of pain mechanisms, the satisfactory management of pathological pain eludes current treatment strategies. We have demonstrated in a previous study on dream deficient mice the pivotal role of downstream regulatory element antagonistic modulator (DREAM) in modulating pain sensitivity in a number of behavioural models, including acute and chronic neuropathic pain. DREAM is a novel calcium binding transcriptional repressor for the prodynorphin gene in spinal cord neurones. The marked attenuation in pain behaviour exhibited by dream-/- mice was shown, by pharmacological and biochemical analyses, to be due to increased activation of the endogenous kappa-opioid system. Importantly, loss of DREAM also attenuated inflammatory pain. Thus, DREAM and the DREAM pathway constitute a novel therapeutic paradigm for the treatment of chronic pain in arthritis.

Nakashima T, Wada T, Penninger JM. · IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria. · Curr Opin Rheumatol. · Pubmed #12707582 No free full text.

Abstract: The TNF-family molecule receptor activator of nuclear factor kappa B (NFkappaB) ligand (RANKL) (OPGL, TRANCE, ODF) and its receptor activator of NFkappaB (RANK) are key regulators of bone remodeling and regulate T cell/dendritic cell communications, and lymph node formation. Moreover, RANKL and RANK are expressed in mammary gland epithelial cells and control the development of a lactating mammary gland during pregnancy. Genetically, RANKL and RANK are essential for the development and activation of osteoclasts and bone loss in response to virtually all triggers tested. Inhibition of RANKL function via the natural decoy receptor osteoprotegerin (OPG, TNFRSF11B) prevents bone loss in postmenopausal osteoporosis and cancer metastases. Importantly, RANKL appears to be the pathogenetic principle that causes bone and cartilage destruction in arthritis, and OPG treatment prevents bone loss at inflamed joints and has partially beneficial effects on cartilage destruction in all arthritis models studied so far. Modulation of these systems provides a unique opportunity to design novel therapeutics to inhibit bone loss and crippling in arthritis.

Alnaeeli M, Penninger JM, Teng YT. · Department of Microbiology and Immunology, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14620, USA. · J Immunol. · Pubmed #16920972 links to  free full text

Abstract: Dendritic cells (DC) are innate immune effectors and are critically involved in regulating T cell immunity. Osteoclasts (OC) are bone-resorbing cells derived from the monocyte/macrophage lineage in response to receptor activator of NF-kappaB ligand (RANKL). DC and T cells form aggregates in the inflammatory infiltrates at active disease sites in human and in experimental rheumatoid arthritis and periodontitis. We investigated whether DC interactions with T cells in the bone environment can support the development of functional OC. In the present study, we demonstrate that upon proper activation by microbial or protein Ags (namely Actinobacillus actinomycetemcomitans, bovine insulin, and outer membrane protein-1) and during immune interactions with CD4+ T cells in vitro, murine BM-derived and splenic CD11c+ DC (CD11b- F4/80- Ly-6C- CD31-) develop into TRAP+ CT-R+ cathepsin-k+ functional OC in a RANKL/RANK-dependent manner. Rescue and blocking experiments using CD11c+ DC derived from Csf-1(-/-) op/op mice show that M-CSF is required "before" developing such osteoclastogenic potential upstream of RANKL/RANK signaling, suggesting that immature CD11c+ DC can indeed act like OC precursors. In addition, these CD11c+ DC-derived OC are capable of inducing bone loss after adoptive transfer in vivo. These data suggest a direct contribution of DC during immune interactions with CD4+ T cells to inflammation-induced osteoclastogenesis. Therefore, our findings not only provide further evidence for DC plasticity, but also extend the current paradigm of osteoimmunology.