Osteoclasts are bone-resorbing cells derived from hematopoietic precursors of the monocyte-macrophage lineage. Regulation of osteoclast function is central to the understanding of bone diseases such as osteoporosis, rheumatoid arthritis and osteopetrosis. Although peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been shown to inhibit osteoblast differentiation, its role, if any, in osteoclasts is unknown. This is a clinically crucial question because PPAR-gamma agonists, "such as thiazolidinediones-" a class of insulin-sensitizing drugs, have been reported to cause a higher rate of fractures in human patients. Here we have uncovered a pro-osteoclastogenic effect of PPAR-gamma by using a Tie2Cre/flox mouse model in which PPAR-gamma is deleted in osteoclasts but not in osteoblasts. These mice develop osteopetrosis characterized by increased bone mass, reduced medullary cavity space and extramedullary hematopoiesis in the spleen. These defects are the result of impaired osteoclast differentiation and compromised receptor activator of nuclear factor-kappaB ligand signaling and can be rescued by bone marrow transplantation. Moreover, ligand activation of PPAR-gamma by rosiglitazone exacerbates osteoclast differentiation in a receptor-dependent manner. Our examination of the underlying mechanisms suggested that PPAR-gamma functions as a direct regulator of c-fos expression, an essential mediator of osteoclastogenesis. Therefore, PPAR-gamma and its ligands have a previously unrecognized role in promoting osteoclast differentiation and bone resorption.

The endocrine hormone fibroblast growth factor 21 (FGF21) is a powerful modulator of glucose and lipid metabolism and a promising drug for type 2 diabetes. Here we identify FGF21 as a potent regulator of skeletal homeostasis. Both genetic and pharmacologic FGF21 gain of function lead to a striking decrease in bone mass. In contrast, FGF21 loss of function leads to a reciprocal high-bone-mass phenotype. Mechanistically, FGF21 inhibits osteoblastogenesis and stimulates adipogenesis from bone marrow mesenchymal stem cells by potentiating the activity of peroxisome proliferator-activated receptor γ (PPAR-γ). Consequently, FGF21 deletion prevents the deleterious bone loss side effect of the PPAR-γ agonist rosiglitazone. Therefore, FGF21 is a critical rheostat for bone turnover and a key integrator of bone and energy metabolism. These results reveal that skeletal fragility may be an undesirable consequence of chronic FGF21 administration.B one is a dynamic tissue that constantly remodels by balancing osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Under physiological conditions, formation and resorption are tightly coupled, thereby maintaining skeletal homeostasis. Under pathological conditions such as osteoporosis or bone metastasis of cancer, the simultaneously decreased formation and increased resorption lead to the uncoupling of remodeling and bone loss (1-3). Osteoblasts are differentiated from bone marrow mesenchymal stem cells (MSCs), which can also differentiate into adipocytes, depending on both extracellular milieu and intracellular signaling (4-8). In contrast, osteoclasts are differentiated from macrophage precursors in the hematopoietic lineage in response to the cytokine Receptor Activator of NF-κB Ligand (RANKL), depending on the ratio of RANKL to osteoprotegerin (OPG), a RANKL decoy receptor that inhibits osteoclast differentiation (9).Fibroblast growth factor 21 (FGF21) is an atypical member of the FGF family that functions as an endocrine hormone (10, 11). It is a powerful regulator of glucose and lipid metabolism. Physiologically, FGF21 expression is induced both in the liver by prolonged fasting through and in the white adipose tissue by feeding through PPAR-γ activation (15-18). Pharmacologically, administration of recombinant FGF21 protein to diabetic mice and rhesus monkeys strongly enhances insulin sensitivity, decreases plasma glucose and triglyceride, and reduces body weight (19)(20)(21)(22)(23). Hence, FGF21 is a potential drug for the treatment of obesity and diabetes that is currently in clinical trials. However, it is unknown whether FGF21 regulates bone mass. This question is clinically important in light of the already increased skeletal fragility in diabetic patients (24, 25) and the reported bone-loss side effects of the current antidiabetic thiazolidinedione (TZD) drugs such as rosiglitazone, a synthetic PPAR-γ agonist (24,(26)(27)(28)(29)). Here we demonstrate that FGF21 is a potent negative regulator of bone, both physiologically and pharmacologically. ...

Macrophages are prominent immune cells in the tumor microenvironment that exert potent effects on cancer metastasis. However, the signals and receivers for the tumor-macrophage communication remain enigmatic. Here, we show that G protein-coupled receptor 132 (Gpr132) functions as a key macrophage sensor of the rising lactate in the acidic tumor milieu to mediate the reciprocal interaction between cancer cells and macrophages during breast cancer metastasis. Lactate activates macrophage Gpr132 to promote the alternatively activated macrophage (M2)-like phenotype, which, in turn, facilitates cancer cell adhesion, migration, and invasion. Consequently, Gpr132 deletion reduces M2 macrophages and impedes breast cancer lung metastasis in mice. Clinically, Gpr132 expression positively correlates with M2 macrophages, metastasis, and poor prognosis in patients with breast cancer. These findings uncover the lactate-Gpr132 axis as a driver of breast cancer metastasis by stimulating tumor-macrophage interplay, and reveal potential new therapeutic targets for breast cancer treatment.reast cancer is the most frequently diagnosed nonskin type of malignancy, and the second leading cause of cancer-related death in women. The 5-y survival rate is 89% in patients who have primary breast cancer, whereas the medium survival of patients with metastatic breast cancer is only 1-2 y (1, 2). Metastasis is the primary cause of breast cancer-related deaths; however, the molecular mechanisms underlying this process are still poorly understood. It has been well established that the tumor microenvironment plays an important role in breast cancer metastasis (3-6). Tumor-associated macrophages (TAMs) make up the largest population of stromal cells that suppress antitumor immunity and foster tumor progression in mouse models of breast cancer (3,(6)(7)(8). TAMs also promote metastasis and correlate with poor prognosis in patients with breast cancer (7, 9). Conversely, TAM functions are also tightly regulated by tumor cells (10, 11). However, the mechanisms underlying this reciprocal regulation between cancer cells and macrophages during metastasis remain elusive.Macrophages are heterogeneous immune cells that can exhibit distinct functions and phenotypes depending on different microenvironment signals (9, 12). They can be broadly divided into classically activated (M1) and alternatively activated (M2) macrophages, the latter of which generally display promalignancy activity (9, 12). In solid tumors, TAMs are usually biased toward M2 (9). Due to hypoxia and glycolytic cancer cell metabolism, the tumor environment is usually acidic, which affects tumor progression by acting on both cancer cells and stromal cells, including macrophages (10,13,14). A recent study shows that cancer cell-derived lactate can educate macrophages to functional TAMs, which, in turn, promotes tumor growth (14). Nonetheless, how lactate activation of TAMs affects cancer metastasis is poorly understood. Importantly, the molecular basis by which macrophages sense and respond t...

Fibroblast growth factor-21 (FGF21) is a hormone secreted by the liver during fasting that elicits diverse aspects of the adaptive starvation response. Among its effects, FGF21 induces hepatic fatty acid oxidation and ketogenesis, increases insulin sensitivity, blocks somatic growth and causes bone loss. Here we show that transgenic overexpression of FGF21 markedly extends lifespan in mice without reducing food intake or affecting markers of NAD+ metabolism or AMP kinase and mTOR signaling. Transcriptomic analysis suggests that FGF21 acts primarily by blunting the growth hormone/insulin-like growth factor-1 signaling pathway in liver. These findings raise the possibility that FGF21 can be used to extend lifespan in other species.DOI: http://dx.doi.org/10.7554/eLife.00065.001