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

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 (TNFTG) 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 TNFTG 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 TNFTG mice fed the rescue diet. Besides, TNFTG 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 TNFTG 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.