RAGE and its ligands in bone metabolism

Abstract

The receptor for advanced glycation end products (RAGE), a member of the immunoglobulin super-family transmembrane proteins, has multiple ligands, thus, is implicated in the pathogenesis of various diseases, including diabetic complications, neurodegenerative disorders, and inflammatory responses. Its function in normal physiology is beginning to be defined, and recent studies have pointed to an important role for RAGE and its ligands (e.g., HMGB1 (high mobility group box 1)) in innate immune response. In addition, RAGE and its ligands are also implicated in osteoclast activation and bone remodeling. Understanding how RAGE and its ligands regulate bone remodeling may provide insight into the pathogenesis of diabetes and chronic inflammation associated bone loss. Recent progress relevant to the functions of RAGE and its ligands in bone remodeling is discussed in this review.

Figure 1

A model to illustrate potential functions of RAGE and HMGB1 in bone remodeling. The bone cells [osteoblasts (OBs), osteoclast (OC), pre-osteoblast (Pre-OB), osteolcast precursor (OCP), and osteocytes) are indicated. RAGE (marked by 3 Ig motifs) is expressed in nearly all of these cells. The extracelluar HMGB1, released from both OCP and Pre-OB, as well as bone marrow macrophages and chondrocytes, promotes OC differentiation in a RAGE dependent manner. HMGB1’s function in OB is unclear. It is suggested that HMGB1 may play a role in recruitment of pre-OBs and OCPs to the site of bone remodeling.