Female-Specific Role of Progranulin to Suppress Bone Formation

Abstract

Progranulin (PGRN) is best known as a glial protein for which deficiency leads to the most common inherited form of frontotemporal dementia. Recently, PGRN has been found to be an adipokine associated with diet-induced obesity and insulin resistance. Therefore, PGRN may have homeostatic effects on bone because PGRN is reported to promote the differentiation of bone-resorbing osteoclasts. We investigated the actions of PGRN on bone using PGRN gene (Grn) knockout (KO) mice and transgenic mice with PGRN mutation and surprisingly found that loss of PGRN prevented the bone loss in female mice induced by aging and estrogen deficiency, whereas it had no effect on male bones during aging. Strikingly, bone formation was increased in female (but not male) PGRN KO mice. We also found that loss of PGRN inhibited bone resorption and osteoclastogenesis in both male and female mice and promoted the production of osteogenic factors in osteoclast lineage cells. These results indicate that PGRN serves to uncouple bone turnover in female mice by promoting bone resorption and suppressing bone formation. Furthermore, we demonstrated that microglial cells/macrophages, but not adipocytes, are an important source of PGRN in producing negative skeletal effects in females. Targeting PGRN production by microglial cells/macrophage-lineage cells may provide a therapeutic approach for the treatment of osteoporosis in females.

Dauricine Protects from LPS-Induced Bone Loss via the ROS/PP2A/NF-κB Axis in Osteoclasts

“…Increased bone resorption was not followed by up-regulated bone formation in LPS-induced bone loss, suggesting an uncoupling of bone remodeling, although a coupled bone remodeling has been shown in ovariectomy -induced [24,28] or cholesterol-induced bone loss [29]. Uncoupled bone remodeling has been reported in myeloma-related bone disease [30], and progranulin-induced bone loss in female mice [31]. In addition, uncoupling has been proposed under prolonged inflammation as a mechanism of periodontal bone loss [32].…”

Erythropoietin Receptor (EPOR) Signaling in the Osteoclast Lineage Contributes to EPO-Induced Bone Loss in Mice

“…Cx3cr1 Cre is relatively more specific to the monocyte/macrophage lineage than LysM Cre , although there are also effects on neutrophils, mast cells, and classical dendritic cells [ 57 ]. These Cx3cr1 Cre mice have been the focus of much recent skeletal research [ 48 , 49 , 58 ], since there is evidence that Cx3cr1 is expressed by osteoclast precursors, which facilitates their recruitment to the BM and is downregulated when they differentiate into mature osteoclasts [ 50 , 59 ].…”

“…One model is based on the LysM Cre construct, which targets the myeloid lineage, including macrophages and preosteoclasts, and is a well-established model for specific recombination starting in early osteoclast progenitors [ 43 , 44 , 45 ]. The second model uses the Cx3cr1 Cre construct, which is more specific to macrophages but is less commonly used to study osteoclast biology [ 46 , 47 , 48 , 49 ].…”

Progranulin is essential for bone homeostasis and immunology

“…Based on the sexual dimorphic bone phenotype in the ovariectomy mouse model, PGRN deficiency in the skeleton was extinguished, indicating that the source of PGRN plays a crucial role in PGRN, especially derived from microglial cells/macrophages. 57 In a murine osteoporosis model, PGRN concentration was regarded as a biomarker of disease.…”

“…Some authors have demonstrated that PGRN deficiency suppressed the expression of mature osteoclast-related genes (cathepsin K [Ctsk] and acid phosphatase 5 [Acp5]), while levels of the early osteoclast gene markers colonystimulating factor 1 receptor and adhesion G protein-coupled receptor E1 were increased. 57 With aging, TRAP and Ctsk levels gradually increased in Pgrn-KO mice, indicating enhanced osteoclastogenesis F I G U R E 2 Functions and signaling pathways associated with PGRN in osteogenesis. PGRN plays dual roles in promoting osteoblast and osteoclast differentiation.…”