Deletion of CD74, a putative MIF receptor, in mice enhances osteoclastogenesis and decreases bone mass

Mun, Se Hwan; Won, Hee Yeon; Hernández, Paula; Aguila, Héctor L.; Lee, Sun Kyeong

doi:10.1002/jbmr.1787

Cited by 47 publications

(50 citation statements)

References 64 publications

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“…Thus, it was reported that the ligation of MIF with its CD74 receptor promotes osteoclastogenesis (20, 21) . On the other hand, it was shown that MIF suppresses osteoclastogenesis as well as CD74-KO mice have an increased capacity to form osteoclasts in vitro as well as in vivo (37, 38) . In the current study it was demonstrated that MIF enhances RANKL-induced osteoclastogenesis in vitro as well as plays an important role in recruitment of OCPs to a particle-induced peripheral bone lesion (Fig.…”

Section: Discussionmentioning

confidence: 99%

Macrophage Migration Inhibitory Factor (MIF) Supports Homing of Osteoclast Precursors to Peripheral Osteolytic Lesions

Movila¹,

Ishii

Albassam

et al. 2016

Journal of Bone and Mineral Research

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By binding to its chemokine receptor CXCR4 on osteoclast precursor cells (OCPs), it is well known that stromal cell-derived factor-1 (SDF-1) promotes the chemotactic recruitment of circulating OCPs to the homeostatic bone remodeling site. However, the engagement of circulating OCPs in pathogenic bone resorption remains to be elucidated. The present study investigated a possible chemoattractant role of macrophage migration inhibitory factor (MIF), another ligand for C-X-C chemokine receptor type 4 (CXCR4), in the recruitment of circulating OCPs to the bone lytic lesion. To accomplish this, we used Csf1r-eGFP-knock-in (KI) mice to establish an animal model of polymethylmethacrylate (PMMA) particle-induced calvarial osteolysis. In the circulating Csf1r-eGFPþ cells of healthy Csf1r-eGFP-KI mice, Csf1rþ/CD11bþ cells showed a greater degree of RANKL-induced osteoclastogenesis compared to a subset of Csf1rþ/RANKþ cells in vitro. Therefore, Csf1r-eGFPþ/CD11bþ cells were targeted as functionally relevant OCPs in the present study. Although expression of the two cognate receptors for MIF, CXCR2 and CXCR4, was elevated on Csf1rþ/CD11bþ cells, transmigration of OCPs toward recombinant MIF in vitro was facilitated by ligation with CXCR4, but not CXCR2. Meanwhile, the level of PMMA-induced bone resorption in calvaria was markedly greater in wild-type (WT) mice compared to that detected in MIF-knockout (KO) mice. Interestingly, in contrast to the elevated MIF, diminished SDF-1 was detected in a particle-induced bone lytic lesion of WT mice in conjunction with an increased number of infiltrating CXCR4þ OCPs. However, such diminished SDF-1 was not found in the PMMA-injected calvaria of MIF-KO mice. Furthermore, stimulation of osteoblasts with MIF in vitro suppressed their production of SDF-1, suggesting that MIF can downmodulate SDF-1 production in bone tissue. Systemically administered anti-MIF neutralizing monoclonal antibody (mAb) inhibited the homing of CXCR4þ OCPs, as well as bone resorption, in the PMMA-injected calvaria, while increasing locally produced SDF-1. Collectively, these data suggest that locally produced MIF in the inflammatory bone lytic site is engaged in the chemoattraction of circulating CXCR4þ OCPs.

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Section: Discussionmentioning

confidence: 99%

Macrophage Migration Inhibitory Factor (MIF) Supports Homing of Osteoclast Precursors to Peripheral Osteolytic Lesions

Movila¹,

Ishii

Albassam

et al. 2016

Journal of Bone and Mineral Research

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“…Bone Marrow Cell Cultures and Osteoclast Formation-Bone marrow cells were isolated from the femurs by a modification of previously published methods (48,49). Briefly, bone marrow cells were collected by centrifugation and washed twice with ␣-minimum essential medium (MEM) (Life Technologies, Inc.) and cultured overnight in ␣-MEM containing 10% FBS.…”

Section: Methodsmentioning

confidence: 99%

Hajdu Cheney Mouse Mutants Exhibit Osteopenia, Increased Osteoclastogenesis, and Bone Resorption

Canalis¹,

Schilling²,

Yee

et al. 2016

Journal of Biological Chemistry

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106

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Notch receptors are determinants of cell fate and function and play a central role in skeletal development and bone remodeling. Hajdu Cheney syndrome, a disease characterized by osteoporosis and fractures, is associated with NOTCH2 mutations resulting in a truncated stable protein and gain-of-function. We created a mouse model reproducing the Hajdu Cheney syndrome by introducing a 6955C3 T mutation in the Notch2 locus leading to a Q2319X change at the amino acid level. Notch2Q2319X heterozygous mutants were smaller and had shorter femurs than controls; and at 1 month of age they exhibited cancellous and cortical bone osteopenia. As the mice matured, cancellous bone volume was restored partially in male but not female mice, whereas cortical osteopenia persisted in both sexes. Cancellous bone histomorphometry revealed an increased number of osteoclasts and bone resorption, without a decrease in osteoblast number or bone formation. Osteoblast differentiation and function were not affected in Notch2 Q2319X cells. The pre-osteoclast cell pool, osteoclast differentiation, and bone resorption in response to receptor activator of nuclear factor B ligand in vitro were increased in Notch2 Q2319X mutants. These effects were suppressed by the ␥-secretase inhibitor LY450139. In conclusion, Notch2 Q2319X mice exhibit cancellous and cortical bone osteopenia, enhanced osteoclastogenesis, and increased bone resorption.Notch proteins are four single-pass transmembrane receptors that play a critical role in cell fate decisions ( Fig. 1) (1-4). Notch regulates cell renewal and plays a role in skeletal development and homeostasis and in osteoblast and osteoclast differentiation (4 -8). Jagged1 and -2 and DeltaLike1, -3, and -4 are the five classic Notch ligands (4). Notch-ligand interactions result in the proteolytic cleavage and release of the Notch intracellular domain (NICD), 2 which translocates to the nucleus to form a complex with recombination signal-binding protein for immunoglobulin J region (Rbpj) and Mastermind-like to regulate transcription (9 -12). This canonical signaling pathway leads to the transcription of Hairy Enhancer of Split (Hes)1, -5, and -7 and Hes related with YRPW motif (Hey)1, -2, and -L. Skeletal cells express Notch1, Notch2, and low levels of Notch3 transcripts (13-15). Activation of Notch in undifferentiated and differentiated osteoblasts inhibits cell differentiation and function and causes osteopenia (16,17). In contrast, activation of Notch1 in osteocytes causes a pronounced increase in bone mass due to a suppression of bone resorption (18). Results from the conditional inactivation of Notch1 and Notch2 in the developing skeleton confirmed the inhibitory role of Notch in osteoblastogenesis (6,19). Whereas substantial work has characterized the consequences of Notch1 gain-of-function in the skeleton, there is limited knowledge on the function of Notch2 in the postnatal skeleton. This knowledge is particularly important because Notch1 and Notch2 do not have redundant functions, and Notch1 inhibits, wh...

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“…Bone marrow-derived cells were seeded onto 96-well plates at a density of 1×10 5 cells/well, and cultured in MEM-α supplemented 10% FBS, 30 ng/ml M-CSF, and 20 ng/ml RANKL for two days [33]. On the third day, the culture medium was replaced by MEM-α supplemented with 10% FBS, 30 ng/ml M-CSF, and 60 ng/ml RANKL, and cells were grown for an additional 3 days.…”

Section: Methodsmentioning

confidence: 99%

“…To determine bone resorption ability of bone marrow-derived cells, a pit formation assay was performed according to the previously described method with minor modifications [33]. UV-sterilized bovine cortical bone slices (120 μm thick) were placed in a bottom of a 24-well plate.…”

Section: Methodsmentioning

confidence: 99%

Knee loading protects against osteonecrosis of the femoral head by enhancing vessel remodeling and bone healing

Liu

et al. 2015

Bone

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Osteonecrosis of the femoral head is a serious orthopedic problem. Moderate loads with knee loading promote bone formation, but its effects on osteonecrosis have not been investigated. Using a rat model, we examined a hypothesis that knee loading enhances vessel remodeling and bone healing through the modulation of the fate of bone marrow-derived cells. In this study, osteonecrosis was induced by transecting the ligamentum teres followed by a tight ligature around the femoral neck. For knee loading, 5 N loads were laterally applied to the knee at 15 Hz for 5 min/day for 5 weeks. Changes in bone mineral density (BMD) and bone mineral content (BMC) of the femur were measured by pDEXA, and ink infusion was performed to evaluate vessel remodeling. Femoral heads were harvested for histomorphometry, and bone marrow-derived cells were isolated to examine osteoclast development and osteoblast differentiation. The results showed that osteonecrosis significant induced bone loss, and knee loading stimulated both vessel remodeling and bone healing. The osteonecrosis group exhibited the lowest trabecular BV/TV (p < 0.001) in the femoral head, and lowest femoral BMD and BMC (both p < 0.01). However, knee loading increased trabecular BV/TV (p < 0.05) as well as BMD and BMC (both p < 0.05). Osteonecrosis decreased the vessel volume, vessel number and VEGF expression (all p < 0.01), and knee loading increased them (all p < 0.01). Osteonecrosis activated osteoclast development, and knee loading reduced its formation, migration, adhesion and the level of “pit” formation (all p < 0.001). Furthermore, knee loading significantly increased osteoblast differentiation and CFU-F (both p < 0.001). A significant positive correlation was observed between vessel remodeling and bone healing (both p < 0.01). These results indicate that knee loading could be effective in repair osteonecrosis of the femoral head in a rat model. This effect might be attributed to promoting vessel remodeling, suppressing osteoclast development, and increasing osteoblast and fibroblast differentiation. In summary, the current study suggests that knee loading might potentially be employed as a non-invasive therapy for osteonecrosis of the femoral head.

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Deletion of CD74, a putative MIF receptor, in mice enhances osteoclastogenesis and decreases bone mass

Cited by 47 publications

References 64 publications

Macrophage Migration Inhibitory Factor (MIF) Supports Homing of Osteoclast Precursors to Peripheral Osteolytic Lesions

Macrophage Migration Inhibitory Factor (MIF) Supports Homing of Osteoclast Precursors to Peripheral Osteolytic Lesions

Hajdu Cheney Mouse Mutants Exhibit Osteopenia, Increased Osteoclastogenesis, and Bone Resorption

Knee loading protects against osteonecrosis of the femoral head by enhancing vessel remodeling and bone healing

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