Models of osteoclast deficiency may help Brigham and Women's Hospital (BWH) scientists understand molecular details and identify potential new drug targets.
People with rheumatoid arthritis suffer painful bone loss at their joints from the autoimmune disease and can lose bone all over from their drugs. To identify better therapeutics for bone loss, scientists need to learn more about the details of bone remodeling. A new mouse model from BWH re-searchers may help.
Bone is continually added by cells called osteoblasts and resorbed back into the body by cells called osteoclasts. It may seem counterintuitive, but the osteoclasts are as necessary to a strong skeleton as the osteoblasts. In addition to their normal continual remodeling, osteoclasts control the localized bone loss at inflamed joints in people with rheumatoid arthritis, as well as general bone loss in osteoporosis.
New Models on Bone Biology
The new mouse model isolates a key transcription factor necessary to transform precursor cells from the bone marrow into osteoclasts in adult mice. But it also is so crucial to heart development that mice without this gene die before birth. Antonios O. Aliprantis, MD, PhD, Instructor in Medicine, Brigham and Women's Hospital, and his colleagues have found a way around this major obstacle with a conditional osteoclast knock-out model.
The conditional knock-out model allows mice to develop normally until day 10, when researchers induce the transcription factor gene, NFATc1, to delete itself. In those mice, bone accumulates near the knee joints and the cartilage calcifies. When Dr. Aliprantis examined these mice more closely he found that they lacked osteoclasts. The model itself provides in vivo evidence of the role of NFATc1 in osteoclast physiology.
Dr. Aliprantis is studying the mice to trace the NFATc1-regulated genes in osteoclasts. "Normally as the myeloid precursors differentiate, they fuse to form multinucleated giant cells that adhere to bone and secrete acid and enzymes that degrade the bone matrix," he said. "Transcription factors like NFATc1 are crucial for this process as they activate the genes necessary to execute this transformation."
The research is conducted in the lab of Laurie H. Glimcher, MD, senior rheumatologist, Division of Rheum-atology, Immunology, and Allergy at BWH, Irene Heinz Given Professor of Immunology, Harvard School of Public Health, and Professor of Medicine, Harvard Medical School. Another team in her bone research group is studying a mouse model of augmented osteoblast activity. Findings in the mice may have relevance for human disease.
Mouse Model Finds Potential Drug Targets for Scleroderma
Therapies for scleroderma have eluded researchers for decades. A recent mouse study has revealed a potential therapeutic target, according to a paper published earlier this year by Dr. Aliprantis and his colleagues in Dr. Glimcher's lab. (PNAS, Vol. 104, 2827-30)
Previous research in mice and people has found a shift in immune cell secretions from an inflammatory cocktail known as type 1 to a pro-fibrotic mix known as type 2. A transcription factor known as T-bet, discovered in the Glimcher lab seven years ago, activates type 1 cytokines and represses type 2 cytokines. (Cell, Vol. 100, 655-669)
Dr. Aliprantis tested how mice missing T-bet responded to bleomycin-induced skin fibrosis. Not surprisingly, they developed more severe fibrosis than mice with the transcription factor. More importantly, Dr. Aliprantis was able to track down the important factor suppressed by T-bet, the profibrotic cytokine interleukin-13 (IL-13). Dr. Aliprantis and his colleagues are following up in the graft-versus-host mouse model, which is more relevant to human scleroderma.
If the findings hold up in further animal studies, this may mean that blocking IL-13 or augmenting T-bet holds promise for human therapeutic use, Dr. Aliprantis said.
Send Feedback to: 
