A rescue diet raises the plasma calcium concentration and ameliorates rheumatoid arthritis in mice: Role of CaSR-mediated inhibition of osteoclastogenesis

Abstract

Calcium modulates bone cell recruitment, differentiation, and function by binding to the calcium-sensing receptor (CaSR). However, the function of CaSR induced by high extracellular calcium (Ca²⁺ _e ) in the regulation of osteoclast formation in rheumatoid arthritis (RA) remains unknown. Here, we used TNFα-transgenic (TNF^TG ) RA mice and their wildtype (WT) littermates fed a normal or a rescue diet (high calcium, high phosphorus, and high lactose diet, termed rescue diet) to compare their joint bone phenotypes. In comparison to TNF^TG mice fed the normal diet, articular bone volume and cartilage area are increased, whereas inflamed area, eroded surface, TRAP⁺ surface, and osteoclast-related genes expression are decreased in TNF^TG mice fed the rescue diet. Besides, TNF^TG mice fed the rescue diet were found to exhibit more CaSR⁺ area and less NFATc1⁺ /TRAP⁺ area. Furthermore, at normal Ca²⁺ _e concentrations, osteoclast precursors (OCPs) from TNF^TG mice formed more osteoclasts than OCPs from WT mice, but the number of osteoclasts gradually decreased when the Ca²⁺ _e concentration increased. Meanwhile, the expression of CaSR increased responding to a high level of Ca²⁺ _e , whereas the expression of NF-κB/NFATc1 signaling molecules decreased. At last, the knockdown of CaSR blocked the inhibition of osteoclast differentiation attributed to high Ca²⁺ _e . Taken together, our findings indicate that high Ca²⁺ _e inhibits osteoclast differentiation in RA mice partially through the CaSR/NF-κB/NFATc1 pathway.

Keywords: TNFα-transgenic mice; calcium; calcium-sensing receptor; osteoclast; rheumatoid arthritis.