Increase of Circulating CD11b⁺Gr1⁺ cells and Recruitment into the Synovium in Osteoarthritic Mice with Hyperlipidemia

Abstract

Although recent studies suggest that hyperlipidemia is a risk factor for osteoarthritis (OA), the link between OA and hyperlipidemia is not fully understood. As the number of activated, circulating myeloid cells is increased during hyperlipidemia, we speculate that myeloid cells contribute to the pathology of OA. Here, we characterized myeloid cells in STR/Ort mice, a murine osteoarthritis model, under hyperlipidemic conditions. Ratios of myeloid cells in bone marrow, the spleen, and peripheral blood were determined by flow cytometry. To examine the influence of the hematopoietic environment, including abnormal stem cells, on the hematopoietic profile of STR/Ort mice, bone marrow transplantations were performed. The relationship between hyperlipidemia and abnormal hematopoiesis was examined by evaluating biochemical parameters and spleen weight of F2 animals (STR/Ort x C57BL/6J). In STR/Ort mice, the ratio of CD11b+Gr1+ cells in spleens and peripheral blood was increased, and CD11b+Gr1+ cells were also present in synovial tissue. Splenomegaly was observed and correlated with the ratio of CD11b+Gr1+ cells. When bone marrow from GFP-expressing mice was transplanted into STR/Ort mice, no difference in the percentage of CD11b+Gr1+ cells was observed between transplanted and age-matched STR/Ort mice. Analysis of biochemical parameters in F2 mice showed that spleen weight correlated with serum total cholesterol. These results suggest that the increase in circulating and splenic CD11b+Gr1+ cells in STR/Ort mice originates from hypercholesterolemia. Further investigation of the function of CD11b+Gr1+ cells in synovial tissue may reveal the pathology of OA in STR/Ort mice.

CD11c+ macrophages and levels of TNF-α and MMP-3 are increased in synovial and adipose tissues of osteoarthritic mice with hyperlipidaemia

“…C57BL/6J and STR/Ort mice were killed by deep anaesthesia and skin was then removed for the harvesting of ST with a scalpel. The harvested ST was digested with 1 mg/ml type I collagenase for 2 h at 37 °C . Perigonadal fat was also harvested from mice and was digested with collagenase D solution (2 mg/ml) (Roche Diagnostics, Indianapolis, IN) for 1–1·5 h at 37 °C .…”

“…Our recent studies have revealed that STR/Ort mice display human hyperlipidaemic-like symptoms, including high serum total cholesterol and triglyceride and hyperinsulinaemia [25,26]. Recently, we reported that myeloid cell populations are increased in the peripheral blood and spleen of STR/Ort mice, and are also recruited into ST [6]. Therefore, characterization of macrophage populations in ST and AT in STR/Ort is expected to provide insight into the relationship between OA pathology and hyperlipidaemia.…”

“…Dyslipidaemia increases the number of circulating myeloid cells which, when recruited into adipose tissue (AT), differentiate into macrophages that contribute to inflammation and insulin resistance upon activation . Synovial inflammation has been implicated in many of the signs and symptoms of OA, including joint swelling and effusion.…”

On the predictive utility of animal models of osteoarthritis

“…However, the variable onset and progression compared with induced models of OA may necessitate greater animal numbers to sufficiently power studies to detect therapeutic effect, and longer treatment times for prophylactic studies and thus more test compound and cost. It is also important to recognize that the underlying mechanisms that drive the onset and progression of spontaneous OA in these animals are not well defined, and may reflect specific subtypes of idiopathic human OA - for example, early SCB remodeling, meniscal ossification and ligament changes in Hartley guinea pigs [ 114 – 117 ] and systemic inflammatory/immune response in STR/Ort mice [ 118 , 119 ].…”

Nerve Growth Factor Regulation by TNF-αand IL-1βin Synovial Macrophages and Fibroblasts in Osteoarthritic Mice

“…STR/Ort mice are a well-characterized OA model that spontaneously develop OA with a progression resembling that of humans [ 22 – 24 ]. Synovial hyperplasia is also observed in STR/Ort mice [ 25 ], and we previously showed that the CD11b+ macrophage population in ST STR/Ort mice is higher than that found in C57BL/6J mice [ 17 , 18 ]. In addition, we reported that compared to synovial fibroblasts (CD11b−), synovial macrophages produce high levels of IL-1 β and TNF- α in STR/Ort mice [ 18 ].…”