Direct inhibitory and indirect stimulatory effects of RAGE ligand S100 on sRANKL‐induced osteoclastogenesis

Abstract

Diabetes results in increased fracture risk, and advance glycation endproducts (AGEs) have been implicated in this pathophysiology. S100 proteins are ligands for the receptor of AGEs (RAGE). An intracellular role of the S100 family member S100A4 (Mts1) to suppress mineralization has been described in pre-osteoblastic MC3T3-E1 cells. However, S100 proteins could have additional effects on bone. The goal of the current study was to determine effects of increased extracellular S100 on osteoclastogenesis. We first determined the direct effects of S100 on pre-osteoclast proliferation and osteoclastic differentiation. RANKL-treated RAW 264.7 cell proliferation and TRAP activity were significantly inhibited by S100, and the number and size of TRAP-positive multinucleated cells were decreased. We then determined whether S100 could affect osteoclastogenesis by an indirect process by examining effects of conditioned media from S100-treated MC3T3-E1 cells on osteoclastogenesis. In contrast to the direct inhibitory effect of S100, the conditioned media promoted RAW 264.7 cell proliferation and TRAP activity, with a trend toward increased TRAP-positive multinucleated cells. S100 treatment of the MC3T3-E1 cells for 14 days did not significantly affect alkaline phosphatase, M-CSF, or OPG gene expression. RANKL was undetectable in both untreated and treated cells. The treatment slightly decreased MC3T3-E1 cell proliferation. Interestingly, S100 treatment increased expression of RAGE by the MC3T3-E1 cells. This suggested the possibility that S100 could increase soluble RAGE, which acts as a decoy receptor for S100. This decrease in availability of S100, an inhibitor of pre-osteoclast proliferation, could contribute to osteoclastogenesis, ultimately resulting in increased bone resorption.

RAGE and its ligands in bone metabolism

“…Its expression is decreased during osteoblast maturation and mineralization; Reduced S100A4 synthesis leads to increased in vitro bone nodule formation (67–68). It is also reported that S100A4 directly inhibit osteoclast differentiation, possibly through its induction of osteoblast production of soluble RAGE (69). In addition to S100A4, S100A6 is found to be increased in osteosarcoma (70).…”

APPswe/Aβ regulation of osteoclast activation and RAGE expression in an age-dependent manner

“…We thus have further investigated functions of RAGE ligands in OC differentiation and activation, and have demonstrated that HMGB1, a proinflammatory cytokine once released from activated macrophages, promotes RANKL induced OC differentiation in a RAGE dependent manner (28). RAGE ligands, AGE and S100, are also found to be involved in regulating osteoclast differentiation directly or indirectly (29,30). However, the function of Aβ in OC differentiation and activation is unknown.…”

VEGF Expression in Diabetic Rats Promotes Alveolar Bone Resorption by <i>Porphyromonas gingivalis</i> LPS

“…Interactions between the AGEs and RAGE result in the dysfunction of immune cells 6,7) and functional alterations of various cells 8,9) , causing cytokine imbalance associated with inflammatory cytokine increases 10,11) . Furthermore, hyperglycemia shifts the balance of the RANKL/OPG interaction in the direction of tissue destruction through AGEs/RAGE interaction 33,34) . This study also indicated that the level of bone resorption due to experimental periodontitis was prominent in rats with diabetes mellitus when compared to that in normal rats.…”