Osteoblast-induced osteoclast apoptosis by fas ligand/FAS pathway is required for maintenance of bone mass

Abstract

The interplay between osteoblasts and osteoclasts has a crucial role in maintaining bone homeostasis. In this study, we reveal that osteoblasts are capable of inducing osteoclast apoptosis by FAS ligand (FASL)/FAS signaling. Conditional knockout of FASL in osteoblasts results in elevated osteoclast numbers and activity, along with reduced bone mass, suggesting that osteoblastproduced FASL is required to maintain physiological bone mass. More interestingly, we show that osteoblasts from ovariectomized (OVX) osteoporotic mice exhibit decreased FASL expression that results from the IFN-γ-and TNF-α-activated NF-κB pathway, leading to reduced osteoclast apoptosis and increased bone resorption. Systemic administration of either IFN-γ or TNF-α ameliorates the osteoporotic phenotype in OVX mice and rescues FASL expression in osteoblasts. In addition, ovariectomy induces more significant bone loss in FASL conditional knockout mice than in control group with increased osteoclast activity in which the levels of RANKL and OPG remain unchanged. Taken together, this study suggests that osteoblast-induced osteoclast apoptosis via FASL/FAS signaling is a previously unrecognized mechanism that has an important role in the maintenance of bone mass in both physiological conditions and OVX osteoporosis.

Osteoblast–osteoclast interactions

“…In addition, using osteoblast progenitor/osteoblast-specific FASL-deficient (FasL cKO) mice, they found that blockage of RANKL showed limited role to reduce the osteoclast activity in FasL cKO mice. Wang et al (Wang et al, 2015) also showed that osteoclast progenitors have lower FAS expression compared with mature osteoclast. Osteoclast progenitors may be low sensitivity to osteoblast-induced apoptosis via FASL/FAS pathway.…”

“…In the presence of MMP3 specific inhibitor, extensive cleavage and soluble FasL concentrations were reduced. Recently, Wang et al (2015) also showed that osteoblasts induce osteoclast apoptosis by FAS ligand (FASL)/FAS signaling. Conditional knockout FasL in osteoblast caused increase of osteoclast number and activity.…”

“…Earlier studies suggested that osteoblast could regulate osteoclast formation (Rodan and Martin, 1981). Subsequently, more and more studies showed that osteoclast can also affect osteoblast activity (Matsuoka et al, 2014; Wang et al, 2015). …”

Using three-point bending to evaluate tibia bone strength in ovariectomized young mice

“…Fas is a transmembrane protein that is associated with the tumor necrosis family (TNF) of receptors that induces apoptosis. Recently, using 12-week-old C57BL/6 mice, Wang et al [28] found that OVX causes a downregulation of FASL in osteoblasts from the femur trabeculae via the proinflammatory cytokines, interferon-γ and TNF-α. They also demonstrated that FASL knockout osteoblasts caused an increase in osteoclast number, which led to a reduction in bone mass.…”

A bone-resorption surface-targeting nanoparticle to deliver anti-miR214 for osteoporosis therapy

“…such as IL2, 61 IL6, 62 TNFα, 63 and IFNγ. 64 Based on our quantification analysis by enzyme-linked immunosorbent assay, serum TNFα, IFNγ, IL2, and IL6 levels were not affected ( Figure 2D). Therefore, it can be inferred that …”