Human osteoclastogenesis in Epstein-Barr virus-induced erosive arthritis in humanized NOD/Shi-scid/IL-2Rγnull mice

Many human viruses, including Epstein-Barr virus (EBV), do not infect mice, which is challenging for biomedical research. We have previously reported that EBV infection induces erosive arthritis, which histologically resembles rheumatoid arthritis, in humanized NOD/Shi-scid/IL-2Rγnull (hu-NOG) mice; however, the underlying mechanisms are not known. Osteoclast-like multinucleated cells were observed during bone erosion in this mouse model, and therefore, we aimed to determine whether the human or mouse immune system activated bone erosion and analyzed the characteristics and origin of the multinucleated cells in hu-NOG mice. Sections of the mice knee joint tissues were immunostained with anti-human antibodies against certain osteoclast markers, including cathepsin K and matrix metalloproteinase-9 (MMP-9). Multinucleated cells observed during bone erosion stained positively for human cathepsin K and MMP-9. These results indicate that human osteoclasts primarily induce erosive arthritis during EBV infections. Human osteoclast development from hematopoietic stem cells transplanted in hu-NOG mice remains unclear. To confirm their differentiation potential into human osteoclasts, we cultured bone marrow cells of EBV-infected hu-NOG mice and analyzed their characteristics. Multinucleated cells cultured from the bone marrow cells stained positive for human cathepsin K and human MMP-9, indicating that bone marrow cells of hu-NOG mice could differentiate from human osteoclast progenitor cells into human osteoclasts. These results indicate that the human immune response to EBV infection may induce human osteoclast activation and cause erosive arthritis in this mouse model. Moreover, this study is the first, to our knowledge, to demonstrate human osteoclastogenesis in humanized mice. We consider that this model is useful for studying associations of EBV infections with rheumatoid arthritis and human bone metabolism.

Download Full-text

Direct stimulation of osteoclastogenesis by MIP-1alpha: evidence obtained from studies using RAW264 cell clone highly responsive to RANKL

Journal of Endocrinology ◽

10.1677/joe.0.1800193 ◽

2004 ◽

Vol 180 (1) ◽

pp. 193-201 ◽

Cited By ~ 93

Author(s):

T Watanabe ◽

T Kukita ◽

A Kukita ◽

N Wada ◽

K Toh ◽

...

Keyword(s):

Bone Marrow ◽

Stromal Cells ◽

Bone Marrow Cells ◽

Tnf Alpha ◽

Adhesion Properties ◽

Multinucleated Cells ◽

Raw264 Cell ◽

Receptor Activator ◽

Rat Bone ◽

Marrow Cells

Macrophage inflammatory protein-1alpha (MIP-1alpha) is a member of the CC chemokines. We have previously reported the use of a whole bone marrow culture system to show that MIP-1alpha stimulates the formation of osteoclast-like multinucleated cells. Here we use rat bone marrow cells deprived of stromal cells, and clones obtained from murine macrophage-like cell line RAW264 to show that MIP-1alpha acts directly on cells in osteoclast lineage. We obtained several types of RAW264 cell clones, one of these clones, designated as RAW264 cell D clone (D clone), showed an extremely high response to receptor activator of NFkappaB ligand (RANKL) and tumor necrosis factor-alpha (TNF-alpha), while the other clone, RAW264 cell N clone (N clone), demonstrated no response to RANKL or TNF-alpha. Although both clones expressed receptor activator NFkappaB (RANK) before being stimulated for differentiation, only the D clone expressed cathepsin K when cells were stimulated to differentiate to osteoclasts. MIP-1alpha stimulated the formation of mononuclear preosteoclast-like cells from rat bone marrow cells deprived of stromal cells. MIP-1alpha also stimulated formation of osteoclast-like multinucleated cells from the D clone, when these cells were stimulated with RANKL and TNF-alpha. These findings provide strong evidence to show that MIP-1alpha acts directly on cells in the osteoclast lineage to stimulate osteoclastogenesis. Furthermore, pretreatment of RAW264 cell D clone with MIP-1alpha significantly induced adhesion properties of these cells to primary osteoblasts, suggesting a crucial role for MIP-1alpha in the regulation of the interaction between osteoclast precursors and osteoblasts in osteoclastogenesis.

Download Full-text

Reversibility of alendronate-induced contraction in human osteoclast-like cells formed from bone marrow cells in culture

Journal of Bone and Mineral Metabolism ◽

10.1007/s007740050071 ◽

1999 ◽

Vol 17 (2) ◽

pp. 98-107 ◽

Cited By ~ 19

Author(s):

Yasuko Koshihara ◽

Shunji Kodama ◽

Hideaki Ishibashi ◽

Yoshiaki Azuma ◽

Tomohiro Ohta ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Cells ◽

Cells In Culture ◽

Human Osteoclast ◽

Marrow Cells

Download Full-text

Multinucleated cells formed on calcified dentine from mouse bone marrow cells treated with 1?,25-dihydroxyvitamin D3 have ruffled borders and resorb dentine

The Anatomical Record ◽

10.1002/ar.1092240307 ◽

1989 ◽

Vol 224 (3) ◽

pp. 379-391 ◽

Cited By ~ 39

Author(s):

Takahisa Sasaki ◽

Naoyuki Takahashi ◽

Shohei Higashi ◽

Tatsuo Suda

Keyword(s):

Bone Marrow ◽

Bone Marrow Cells ◽

Mouse Bone Marrow ◽

Dihydroxyvitamin D3 ◽

Multinucleated Cells ◽

Mouse Bone Marrow Cells ◽

Marrow Cells

Download Full-text

Effects and Interaction of Icariin, Curculigoside, and Berberine in Er-Xian Decoction, a Traditional Chinese Medicinal Formula, on Osteoclastic Bone Resorption

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/490843 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 15

Author(s):

Liming Xue ◽

Lei Jiao ◽

Yin Wang ◽

Yan Nie ◽

Ting Han ◽

...

Keyword(s):

Bone Marrow ◽

Bone Resorption ◽

Bone Marrow Cells ◽

Cathepsin K ◽

Osteoclastic Bone Resorption ◽

Tartrate Resistant Acid Phosphatase ◽

Inhibitory Effects ◽

Dihydroxyvitamin D ◽

Marrow Cells

Er-Xian decoction (EXD), a traditional Chinese medicine, has been reported to have a protective effect against bone loss in ovariectomized osteoporotic rats, and the inclusion of icariin (I), curculigoside (C), and berberine (B) in EXD displays inhibitory effects on osteoclastic bone resorption. In the present paper, we investigated the interaction and effects of I, C, B, and their combination on bone resorption activityin vitroon osteoclasts derived from rat bone marrow cells. ICB synergistically decreased the formation of bone resorption pits, the number of multinucleated osteoclasts, and the activity of tartrate-resistant acid phosphatase (TRAP) and showed antagonistic or additive effects on cathepsin K activity in the coculture system of osteoblasts and bone marrow cells in the presence of 1, 25-dihydroxyvitamin D3and dexamethasone. The combination of ICB also enhanced the inhibitory effects on the formation of F-actin ring, a cytoskeleton structure of osteoclasts induced from bone marrow cells with macrophage colony stimulation factor (M-CSF) and receptor activator of NF-κB ligand (RANKL). In addition, ICB synergistically improved the ratio of protein expression of osteoprotegerin (OPG) and RANKL in osteoblasts and interfered with the mitogen-activated protein kinases (MAPKs) pathway in osteoclast. These results clearly show that I, C, B, and their combination in EXD exert effects of mutual reinforcement. However, IBC does not show an intensified adverse effect in the ovariectomized murine model, as revealed by change in body and uterine weight, confirming the safety of EXD. These observations are in agreement with the rationality of the formula used in this paper.

Download Full-text