Taking a Toll on the bones: Regulation of bone metabolism by innate immune regulators

The interplay between the immune system and bone metabolism has been recognized as important for both of these systems. Various factors produced and released during immune responses markedly affect bone cells and bone metabolism. Meanwhile, niches for lymphocytes in bone also play an important role in the biology of these cells. Osteoimmunology, a new area of research focusing on associations between the immune and bone systems, is based on the concept that deeper investigation of the relationships between these systems will enhance our understanding of their biology and contribute to the discovery of novel therapeutic approaches for diseases of the two systems. Toll-like receptors (TLRs), the focus of this review, sense pathogen-derived molecules and initiate the inflammatory reactions of innate immune cells. TLRs are also expressed in bone cells, and their activation affects osteoclast differentiation and activity in a complex manner: TLR activation in early osteoclast precursors blocks the differentiation of those cells, while in cells that have already started their osteoclastic differentiation, it stimulates this process and increases the survival rates of mature osteoclasts (OCs). Activation of TLRs in osteoblasts (OBs) induces the production of osteoclastogenic cytokines, such as RANKL and TNF-alpha, thereby contributing to TLR ligand-induced osteoclastogenesis. These processes are the reason for the bone loss observed in variety of infectious diseases. The inhibition of osteoclastogenesis by TLR activation in early precursor cells may play a role in reducing the excessive bone loss caused by pathogenic infection and shifting the balance between the bone and immune systems during infection to recruit immune cells.