Ovariectomy disregulates osteoblast and osteoclast formation through the T-cell receptor CD40 ligand

Abstract

The bone loss induced by ovariectomy (ovx) has been linked to increased production of osteoclastogenic cytokines by bone marrow cells, including T cells and stromal cells (SCs). It is presently unknown whether regulatory interactions between these lineages contribute to the effects of ovx in bone, however. Here, we show that the T-cell costimulatory molecule CD40 ligand (CD40L) is required for ovx to expand SCs; promote osteoblast proliferation and differentiation; regulate the SC production of the osteoclastogenic factors macrophage colony-stimulating factor, receptor activator of nuclear factor-κB ligand, and osteoprotegerin; and upregulate osteoclast formation. CD40L is also required for ovx to activate T cells and stimulate their production of TNF. Accordingly, ovx fails to promote bone loss and increase bone resorption in mice depleted of T cells or lacking CD40L. Therefore, cross-talk between T cells and SCs mediated by CD40L plays a pivotal role in the disregulation of osteoblastogenesis and osteoclastogenesis induced by ovx.estrogen | osteoporosis M enopause results in decreased production of estrogen (E) and a parallel increase in FSH levels, which together stimulate bone resorption (1) and cause a period of rapid bone loss that is central for the onset of postmenopausal osteoporosis (2). The acute effects of menopause are modeled by ovariectomy (ovx) which, like natural menopause, stimulates bone resorption by increasing osteoclast (OC) formation (3, 4) and lifespan (5, 6). The net bone loss caused by ovx is limited by an increase in bone formation resulting from stimulated osteoblast (OB) formation (7). This compensation is fueled by an expansion of the pool of bone marrow (BM) stromal cells (SCs), increased commitment of SCs to the osteoblastic lineage (7), and enhanced proliferation of early OB precursors (8). The stimulatory effect of ovx on SCs is equally relevant for osteoclastogenesis because one of the consequences of E deprivation is the formation of osteoblastic cells with increased osteoclastogenic activity (9), that is, the capacity to support OC formation.OC formation occurs when bone marrow macrophages (BMMs) are stimulated by the osteoclastogenic factors receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) (10, 11); however, in conditions of E deficiency, the secretion of the RANKL decoy receptor osteoprotegerin (OPG) decreased (12

Increasing dietary nitrate has no effect on cancellous bone loss or fecal microbiome in ovariectomized rats

“…Sex steroid deficiency results in a chronic inflammatory state that may contribute to osteoporosis 71. The microbiome's effects on bone mass may be mediated via alteration of the immune system and regulation of osteoclastogenesis, which results in greater bone loss in postmenopause when women lose the immunosuppressive effects of estrogen 30, 72, 73. This evidence suggests a putative role of the gut microbiome in the bone loss observed in sex‐steroid deficiency.…”

Osteoimmunology: from mice to humans

“…This results in a significant increase in osteoclastogenesis. 38 This mechanism has been demonstrated in mice but has not been confirmed in humans. Nevertheless, some papers confirm the role of estrogen in the regulation of immune function in humans in healthy or different disease states.…”

“…1 During estrogen deficiency the immune response is altered and, in particular, T cells become more active and able to produce inflammatory and pro-osteoclastogenic cytokines such as TNFa and RANKL. Despite some inverse reports, 34,35 the main body of literature firmly supports the essential role of activated T cells in regulating bone loss induced by estrogen deficiency, 5,[36][37][38] both in animal models and in humans.…”

“…B-cell knockout mice are osteoporotic with enhanced osteoclastic bone resorption due to decreased OPG level. 47 B-cell OPG production is upregulated by the activation of CD40; 38 thus, T-cell signaling to B cells, through CD40L and CD40, has an important role in regulating basal OC formation and in regulating bone homeostasis. During estrogen deficiency the upregulation of CD40 enhances the cross-talk between T and B cells.…”

Interplay between Mesenchymal Stem Cells and Lymphocytes

“…Similarly, activated T-lymphocytes impair orofacial bone/bone-marrow-derived MSCs (OMSCs), suggesting that OMSCs are capable of interacting with systemic immunity (Yamaza et al, 2011). In addition, T-cells induce bone marrow MSC and osteoblast apoptosis through the CD40/ CD40L pathway, as observed in some bone-disease-related animal models, such as osteoporosis (Li et al, 2011). Conversely, immune components have been proven to regulate the differentiation of MSCs.…”