The HIV co-receptor CCR5 regulates osteoclast function

Ji-Won Lee,Kazuki Inoue,Akiyoshi Hoshino,Shunsuke Uehara,Akira Yamaguchi,Yuuki Imai,Takashi Saitou,Tadahiro Iimura,Yasuhiro Kobayashi,Kouji Matsushima,Satoshi Ueha

doi:10.1038/s41467-017-02368-5

Abstract

C–C chemokine receptor 5 (CCR5) is a co-receptor of HIV. Epidemiological findings suggest that the functional loss of CCR5 is correlated with a lower incidence of bone-destructive diseases as well as of HIV transmission. However, it is not clear whether CCR5 is involved in regulation of the function of bone cells, in addition to that of immune cells. Here we show that blockade of CCR5 using specific antibodies impairs human osteoclast function in vitro. Ccr5-deficient (Ccr5−/−) mice presented with dysfunctional osteoclasts and were resistant to osteoporosis induced by receptor activator of nuclear factor kappa-B ligand (RANKL), which triggers osteoporosis independently of inflammatory and immunomodulatory pathways. Furthermore, Ccr5 deficiency impairs the cellular locomotion and bone-resorption activity of osteoclasts, which is associated with the disarrangement of podosomes and adhesion complex molecules including Pyk2. Overall, the data provides evidence that CCR5 has an essential role in bone-destructive conditions through the functional regulation of osteoclasts.

Highlights

C–C chemokine receptor 5 (CCR5) is a co-receptor of HIV
A number of epidemiological studies have demonstrated that non-functional CCR5 is associated with lower HIV transmission, and with the reduced severity rheumatoid arthritis (RA) and/or a lower frequency of RA development[13,14,15,16,17], collectively suggesting that CCR5 is a suitable target for RA therapy
The tartrate-resistant acid phosphatase (TRAP) level was significantly augmented by the injection of receptor activator of nuclear factor kappa-B ligand (RANKL), but to less extent compared to that in their wild-type littermates. These analyses indicated that Ccr5−/− mice were more resistant to sRANKLinduced osteoporosis than their wild-type littermates

Summary

Introduction

Epidemiological findings suggest that the functional loss of CCR5 is correlated with a lower incidence of bone-destructive diseases as well as of HIV transmission. In the pathogenesis of RA, CCR5 is preferentially expressed in T cells, monocytes, and macrophages, thought to have pro-inflammatory role This hypothesis remains controversial as many background factors in the distinct inflammatory mechanisms and immune responses of individual patients may obscure the association between the loss of the CCR5 function and the development of RA. Our findings demonstrate that CCR5 is required for the functional cellular architecture of osteoclasts through regulating integrin- and chemokine-mediated pathways, thereby elucidating the direct association between loss of CCR5 and resistance to bone loss in mice

Methods

Results

Conclusion