The deficiency of immunoregulatory receptor PD-1 causes mild osteopetrosis
| Autor: | Kazuhiro Aoki, Mariko Takahashi, K. Nagahama, Bobby John Varghese, Keiichi Ohya, Hiroaki Saito, Hitoyata Shimokawa, Kiichi Nonaka, Kimie Ohyama, Miyuki Azuma |
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| Rok vydání: | 2004 |
| Předmět: |
medicine.medical_specialty
Histology Physiology Endocrinology Diabetes and Metabolism T cell Programmed Cell Death 1 Receptor Gene Expression Osteoclasts Bone Marrow Cells Biology Bone remodeling Metabolic bone disease Mice Bone Density Osteoclast Internal medicine medicine Animals Cytotoxic T cell Mice Knockout Osteoblasts Tibia Macrophages Cell Differentiation Osteopetrosis medicine.disease Mice Inbred C57BL Osteopenia Phenotype medicine.anatomical_structure Endocrinology Antigens Surface Cortical bone Apoptosis Regulatory Proteins |
| Zdroj: | Bone. 35:1059-1068 |
| ISSN: | 8756-3282 |
| DOI: | 10.1016/j.bone.2004.06.018 |
| Popis: | Recently, the involvement of immune responses in metabolic bone disease and/or local bone destruction has received much attention. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a member of the immunoglobulin (Ig) superfamily, negatively regulates T cell activation. The deficiency of CTLA-4 induces profound osteopenia with an increase in osteoclastogenesis, suggesting the important role of activated T cells in osteoclastogenesis. Programmed death-1 (PD-1) is the newly identified immunoregulatory receptor, which also belongs to the Ig superfamily. Both CTLA-4 and PD-1 are induced on activated T cells, however, there are no reports linking PD-1 with osteoclasts. In the present study, we have examined the bone phenotype in PD-1-deficient mice PD-1-/- and the role of PD-1 in osteoclastogenesis and osteoclast function. Both trabecular and cortical bone mineral densities of tibia were significantly increased, as observed in peripheral quantitative computed tomography (pQCT), at 12 weeks of age in PD-1-/- mice. Histomorphometric analysis of the PD-1-/- mice and the age-matched controls at 12 weeks of age showed a 2-fold increase in bone volume (BV/TV) with a 55% decrease in osteoclast number (N.Oc/BS). Bone formation indices were similar in both groups. The number of soluble receptor activator of nuclear factor kappaB ligand (sRANKL)-induced osteoclast-like cells (OCLs) derived from the PD-1-deficient splenocytes was significantly decreased (by 25%). On the other hand, PD-1 deficiency did not affect the bone-resorbing activity of mature osteoclasts. Our results suggest that PD-1 deficiency reduces osteoclastogenesis resulting in an osteopetrotic phenotype. Identical members of the Ig superfamily, CTLA-4 and PD-1, which negatively regulate immune responses, may differentially affect osteoclastogenesis and bone remodeling. |
| Databáze: | OpenAIRE |
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