Immunology of Osteoporosis: A Short-Review

The osteoporosis pathogenesis is multifactorial and the immune system has an important role. Free radicals and the proteins or lipids that become glycated after exposure to sugars that may be related with bone resorption and inflammation. It is now recognized that the receptor activator of NF-κB ligand (RANKL) has a major role at the bone resorbing. The physiological receptor of the biological activity of RANKL is managed by osteoprotegerin (OPG). The balance of RANKL and OPG in physiological bone turnover may control the bone density and pathological conditions. This review aims to provide a short overview of osteoimmunology in osteoporosis .

OPG is a member of the tumor necrosis factor (TNF) receptor family and a cytokine receptor. By binding to RANKL and prevent it from binding receptor RANK, OPG protects the bones from excessive resorption. Therefore, the relationship between RANKL and OPG is the major marker of the bone density and bone integrity. Genetic experiments on these molecules have been emphasizing how important it is to fulfil the function of osteoclasts and osteoclast development (5,6). RANK has been discovered as an important ingredient in epithelial growth and cell differentiation. RANK is necessary for the formation of mammary glands, thymic epithelial cells and intestinal cells. Also, it has been shown to play a role in the pathogenesis of some forms of cancer (7)(8)(9). The increase in RANK expression in some types of cancer such as breast and colon cancer brought the allegations to be associated with RANKL.
RANK -RANKL pathway targeting drugs may revolutionize the treatment of arthritis, bone loss, oral squamous cell carcinoma and some cancer metastasis (10,11). OPG is released from many tissues including heart, lung, kidney, liver, brain, spinal cord, thyroid gland, stomach, intestines, bone and smooth muscle. And there are many functions that represent multiple possible functions. OPG's most important role is to protect the bone tissue (12).

Bone Remodeling
Bone remodeling is a process operating under the control of a variety of systemic and local factors of production function of osteoblasts and destruction function of osteoclasts Parathyroid hormone (PTH) is a major regulator of homeostasis of calcium ions (13). This hormone is mainly increases blood calcium concentration by acting on parathyroid hormone 1 receptors. PTH is secreted into the circulation in response to low blood calcium levels and show various effects on intestine, kidney and bone. PTH regulates the activation, survival and differentiation of osteoclast and also release of interleukin-6 and RANKL by osteoblasts, in bone (12,14).

Role of B and T lymphocytes in bone
In vitro and in vivo studies shows that, T lymphocytes activated by estrogen deficiency in postmenopausal osteoporosis can causes an increase in production of tumor necrosis factor alpha (TNF -A). In the absence of estrogen, TNF-producing T cells have a very important role in bone loss by the cytokines including, interleukin -7, transforming growth factor-B and Interferon -G (15,16). TNF directly and substantially increasing the sensitivity of the mature osteoclast to RANKL and macrophage colony stimulating factor by the way increase osteoclast formation and bone resorption. While TNF stimulates osteoclastic activity inhibits other hand osteoblastogenesis (17,18). In one study, bone loss would lead to the increased secretion of RANKL in B and T cells have been suggested (19). B lymphocytes are known to play a role in regulation of osteoclast formation and bone resorption and also play a role RANK / RANKL / OPG system active regulation (20). In another study, percentage of CD5 + B cells with have been demonstrated to be correlated CTX-1 serum level which is an indicator of the bone resorption in rheumatoid arthritis patients (21). In a study found that; CD19 + B lymphocytes and memory B cells were significantly lower number of various subpopulations in women with osteoporosis than in healthy controls (22).
The Wnt signaling pathway and Biology of sclerostin Wnt signaling system is very important in the embodiment of bone development and bone mass. Wnt signaling loss due to mutations can lead to loss of bone mass. Sclerostin inhibits bone formation by blocking Wnt pathway (23)(24)(25).

Therapeutic Aspects
Recently RANKL / RANK / OPG system is more focused on targeted therapies. Denosumab is a monoclonal antibody molecule that targets RANKL recently developed by the pharmaceutical industry. This drug is a monoclonal IgG antibody which is genetically engineered in hamster ovary cells. It has high affinity to bind RANKL, the principle regulator of resorption (26). This drug inhibits osteoclast activity and production and in clinical trials showed that denosumab reduces bone resorption and improves bone mineral density (27). Denosumab significantly decreased the risk of osteoporotic vertebral and nonvertebral fractures in postmenopausal women (28). Early and preclinical researches showed that sclerostin inhibitors can assist the bone formation and may be a new method of treatment for osteoporotic bone. One of the Sclerostin inhibitor molecules is romosozumab. A study showed that subcutaneous or intravenous injection of romosozumab can decrease bone turnover markers. Compared with placebo, treatment of romosozumab been shown to have positive effects on both cortical and trabecular bone mass (29, 30). Another sclerostin inhibitor molecule is blosozumab. In a study single or multiple doses blosozumab given up to 8 weeks in postmenopausal women subcutaneously or intravenously and showed increase dose dependent lumbar densitometry scores but total hip scores did not change significantly (31). In an Another study about blosozumab treatment showed that; in total hip and