Interferon-γ plays a role in bone formation in vivo and rescues osteoporosis in ovariectomized mice

Duque, Gustavo; Huang, Dao Chao; Dion, Natalie; Macoritto, Michael; Rivas, Daniel; Li, Wei; Xj, Yang; Li, Jiarong; Lian, Jing; Marino, Faleh Tamim; Barralet, Jake E.; Lascau, Viorica; Deschênes, Claire; Ste‐Marie, Louis‐Georges; Kremer, Richard

doi:10.1002/jbmr.350

Cited by 147 publications

(124 citation statements)

References 51 publications

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“…Although bone mass is decreased in Ifngr -/-mice, this appears to be primarily a defect in bone formation, and osteoclast number is not increased (49). Neither IFN-γ nor IFN-γR deficiency substantially affected BM OCP frequency or number (J.F.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory arthritis increases mouse osteoclast precursors with myeloid suppressor function

Charles

Hsu²,

Niemi³

et al. 2012

J. Clin. Invest.

143

145

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Increased osteoclastic bone resorption leads to periarticular erosions and systemic osteoporosis in RA patients. Although a great deal is known about how osteoclasts differentiate from precursors and resorb bone, the identity of an osteoclast precursor (OCP) population in vivo and its regulatory role in RA remains elusive. Here, we report the identification of a CD11b -/lo Ly6C hi BM population with OCP activity in vitro and in vivo. These cells, which can be distinguished from previously characterized precursors in the myeloid lineage, display features of both M1 and M2 monocytes and expand in inflammatory arthritis models. Surprisingly, in one mouse model of RA (adoptive transfer of SKG arthritis), cotransfer of OCP with SKG CD4 + T cells diminished inflammatory arthritis. Similar to monocytic myeloid-derived suppressor cells (M-MDSCs), OCPs suppressed CD4 + and CD8 + T cell proliferation in vitro through the production of NO. This study identifies a BM myeloid precursor population with osteoclastic and T cell-suppressive activity that is expanded in inflammatory arthritis. Therapeutic strategies that prevent the development of OCPs into mature bone-resorbing cells could simultaneously prevent bone resorption and generate an antiinflammatory milieu in the RA joint. IntroductionOsteoclasts are the primary bone-resorbing cell and are essential for physiologic bone remodeling. In the absence of either RANK or its ligand RANKL, the essential receptor-ligand pair for osteoclast differentiation and survival, mice lack osteoclasts and have severe osteopetrosis with absence of tooth eruption (1-3). Osteoclasts are myeloid lineage cells that also require M-CSF for differentiation and survival (4, 5). Osteoclasts can be cultured in vitro from BM, peripheral blood, or spleen cells in the presence of M-CSF and RANKL. Although BM CD11b -/lo CD115 + CD117 + cells are enriched in osteoclast differentiation activity (6, 7), the cell-surface phenotype and biology of the BM osteoclast precursor (OCP) and its relationship to other myeloid lineages has not been characterized in depth.The common monocyte DC precursor (MDP) was described as having the cell-surface phenotype CD11b -CD115 + CD117 int (8), and differentiation of monocytes and DCs from MDPs has been intensely studied (reviewed in ref. 9). It is likely that MDPs can also differentiate into osteoclasts, as a population with a similar surface phenotype is capable of differentiation into osteoclasts, macrophages, or DCs, depending on cytokine conditions (6, 10). Recent work confirmed the primary BM OCPs as CD11b -/lo CD115 + CD117 + , although CD117 -cells were also able to differentiate into osteoclasts less efficiently (6, 7). BM OCPs in the human TNFA Tg (hTNF-α-Tg) mouse were identified by others as characterized by the markers CD11b + and Gr-1 -, using the 1A-8 antibody that is specific for the granulocyte Ly6G receptor, the main component of the Gr-1 epitope (11). Recent studies have identified a circulating quiescent lin-

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Section: Discussionmentioning

confidence: 99%

Inflammatory arthritis increases mouse osteoclast precursors with myeloid suppressor function

Charles

Hsu²,

Niemi³

et al. 2012

J. Clin. Invest.

143

145

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“…(1,3) An effective bone anabolic agent would induce bone formation by stimulating osteoblast activity, by protecting osteoblasts against premature death, and by promoting the differentiation of MSC down the osteoblast rather than the adipocyte lineage. (1) In fact, several studies have demonstrated that it is possible to stimulate osteoblast differentiation at the expense of adipogenesis using compounds such as parathyroid hormone, (18) interferon gamma, (19,20) and strontium ranelate. (21) The active metabolite of vitamin D, 1,25(OH) 2 D 3 , has also been shown to stimulate bone formation by promoting osteoblastogenesis (12) and inhibiting adipogenesis (17) in a murine model of age-related bone loss.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of PPARγ increases osteoblastogenesis and bone mass in male C57BL/6 mice

Duque

Vidal

et al. 2012

Journal of Bone and Mineral Research

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Infiltration of bone marrow with fat is a prevalent feature in people with age-related bone loss and osteoporosis, which correlates inversely with bone formation and positively with high expression levels of peroxisomal proliferator-activated receptor gamma (PPARg). Inhibition of PPARg thus represents a potential therapeutic approach for age-related bone loss. In this study, we examined the effect of PPARg inhibition on bone in skeletally mature C57BL/6 male mice. Nine-month-old mice were treated with a PPARg antagonist, bisphenol-A-diglycidyl ether (BADGE), alone or in combination with active vitamin D (1,25[OH] 2 D 3 ) for 6 weeks. Micro-computed tomography and bone histomorphometry indicated that mice treated with either BADGE or BADGE þ 1,25(OH) 2 D 3 had significantly increased bone volume and improved bone quality compared with vehicle-treated mice. This phenotype occurred in the absence of alterations in osteoclast number. Furthermore, the BADGE þ 1,25(OH) 2 D 3 -treated mice exhibited higher levels of unmineralized osteoid. All of the treated groups showed a significant increase in circulating levels of bone formation markers without changes in bone resorption markers, while blood glucose, parathyroid hormone, and Ca þ remained normal. Furthermore, treatment with BADGE induced higher levels of expression of vitamin D receptor within the bone marrow. Overall, treated mice showed higher levels of osteoblastogenesis and bone formation concomitant with decreased marrow adiposity and ex vivo adipogenesis. Taken together, these observations demonstrate that pharmacological inhibition of PPARg may represent an effective anabolic therapy for osteoporosis in the near future. ß

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“…When ovariectomized, sham-operated, and intact lactating rats were each stressed by a 0.1% calcium diet, there was no difference in the reduction of femoral ash weight among the groups (32). Ovariectomy to create estradiol deficiency leads to modest and slow bone loss in rodents, and not to the rapid loss that occurs during lactation (22,34,260). Conversely, treatment with estradiol to achieve fivefold higher levels than normal during lactation blunted bone loss and caused a small decline in milk calcium (956).…”

Section: Animal Datamentioning

confidence: 99%

Maternal Mineral and Bone Metabolism During Pregnancy, Lactation, and Post-Weaning Recovery

Kovacs

2016

Physiological Reviews

383

524

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During pregnancy and lactation, female physiology adapts to meet the added nutritional demands of fetuses and neonates. An average full-term fetus contains ϳ30 g calcium, 20 g phosphorus, and 0.8 g magnesium. About 80% of mineral is accreted during the third trimester; calcium transfers at 300-350 mg/day during the final 6 wk. The neonate requires 200 mg calcium daily from milk during the first 6 mo, and 120 mg calcium from milk during the second 6 mo (additional calcium comes from solid foods). Calcium transfers can be more than double and triple these values, respectively, in women who nurse twins and triplets. About 25% of dietary calcium is normally absorbed in healthy adults. Average maternal calcium intakes in American and Canadian women are insufficient to meet the fetal and neonatal calcium requirements if normal efficiency of intestinal calcium absorption is relied upon. However, several adaptations are invoked to meet the fetal and neonatal demands for mineral without requiring increased intakes by the mother. During pregnancy the efficiency of intestinal calcium absorption doubles, whereas during lactation the maternal skeleton is resorbed to provide calcium for milk. This review addresses our current knowledge regarding maternal adaptations in mineral and skeletal homeostasis that occur during pregnancy, lactation, and post-weaning recovery. Also considered are the impacts that these adaptations have on biochemical and hormonal parameters of mineral homeostasis, the consequences for long-term skeletal health, and the presentation and management of disorders of mineral and bone metabolism.

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Interferon-γ plays a role in bone formation in vivo and rescues osteoporosis in ovariectomized mice

Cited by 147 publications

References 51 publications

Inflammatory arthritis increases mouse osteoclast precursors with myeloid suppressor function

Inflammatory arthritis increases mouse osteoclast precursors with myeloid suppressor function

Pharmacological inhibition of PPARγ increases osteoblastogenesis and bone mass in male C57BL/6 mice

Maternal Mineral and Bone Metabolism During Pregnancy, Lactation, and Post-Weaning Recovery

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