Excessive osteoclast activity leads to bone loss in many immune disorders. Although bone loss is typically associated with osteopenic disorders, it may also be associated with leukemias and infections suggesting that activation of T cells affects bone physiology. Activated T cells can increase numbers of osteoclasts and reduce bone mineral density both in vitro and in vivo.1 Following antigen receptor engagement, T cells express osteoprotegerin ligand (OPGL).2 OPGL is also known as TRANCE, TNFSF11, RANKL, or ODF. Resting T cells do not express OPGL. OPGL induces bone marrow precursors to develop into osteoclasts demonstrating bioactivity in vitro.
The receptor for OPGL, osteoprotegerin (OPG), also known as TNFRSF11B, OCIF, or RANK, contains no transmembrane domain and circulates as a homodimer acting as a decoy receptor. OPG is able to block development of osteoclastogenesis. OPG-knockout mice exhibit severe osteoporosis.
The ctla4-/- mouse shows spontaneous T cell activation and also displays severe osteoporosis. Transfer of bone marrow cells from ctla4-/- into lymphocyte deficient mice (rag1-/-) causes a decrease in bone mineral density and increased numbers of osteoclasts. Injections of ctla4-/- mice with OPG increase bone mineral density and reduce osteoclast numbers. This demonstrates that systemic activation of T cells can lead to bone loss in vivo through OPGL.
Adjuvant arthritis is a rat model which mimics many of the features of human rheumatoid arthritis. It is induced by subcutaneous injection of Mycobacterium tuberculosis. Rats develop severe inflammation in bone marrow, extensive local bone and cartilage destruction, and loss of bone mineral density. The lesions are strictly dependent on T cell activation. Treatment of rats with OPG abrogates loss of bone mineral density by preventing accumulation of osteoclasts. It also preserves cartilage integrity. T cells isolated from human patients with rheumatoid arthritis or osteoarthritis express OPGL.
Mice lacking T and B cells exhibit normal bone morphology and density, implying T cells are not required for normal bone homeostasis. Inflammation, however, attracts T cells that then actively participate in bone remodelling via OPGL. This may offer insight into bone loss associated with autoimmune disease and infection where T cells are activated. Inhibition of OPGL function offers a potential therapeutic target for osteopenic disorders.