Significance: Metastasis is a major cause of cancer mortality. However, the regulation of this complex process remains poorly understood. Due to low oxygen supply and enhanced sugar metabolism, cancer cells releases lactate to create an acidic environment. We show that a membrane receptor on macrophages called G protein-coupled receptor 132 (Gpr132) can sense and respond to this lactate signal from cancer cells. As a result, macrophages alter their functions, which, in turn, stimulates cancer metastasis to distant organs. Consequently, loss of Gpr132 in mice inhibits breast cancer metastasis; lower Gpr132 expression in patients with breast cancer correlates with better metastasis-free survival. These findings uncover knowledge and potentially novel treatment for cancer metastasis.

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.

A microRNA, miR-34a, is a novel and critical suppressor of osteoclastogenesis, bone resorption and the bone metastatic niche. Osteoclast cells are involved in bone resorption, and therefore have a role in osteoporosis and bone metastasis. Yihong Wan and colleagues identify a microRNA, miR-34a, whose expression regulates osteoclastogenesis. Upregulation or transgenic expression of miR-34a is associated with lower bone resorption, and therefore increased bone mass. One target of miR-34a relevant to this process is Tgif2, a pro-osteoclastogenic transcriptional regulator; its deletion restores bone mass in a miR-34a-independent manner. This work points to miR-34a — commonly deleted in cancers — as having potential therapeutic benefits for skeletal protection and strategies to ameliorate bone metastasis of cancers. Bone-resorbing osteoclasts significantly contribute to osteoporosis and bone metastases of cancer1,2,3. MicroRNAs play important roles in physiology and disease4,5, and present tremendous therapeutic potential6. Nonetheless, how microRNAs regulate skeletal biology is underexplored. Here we identify miR-34a as a novel and critical suppressor of osteoclastogenesis, bone resorption and the bone metastatic niche. miR-34a is downregulated during osteoclast differentiation. Osteoclastic miR-34a-overexpressing transgenic mice exhibit lower bone resorption and higher bone mass. Conversely, miR-34a knockout and heterozygous mice exhibit elevated bone resorption and reduced bone mass. Consequently, ovariectomy-induced osteoporosis, as well as bone metastasis of breast and skin cancers, are diminished in osteoclastic miR-34a transgenic mice, and can be effectively attenuated by miR-34a nanoparticle treatment. Mechanistically, we identify transforming growth factor-β-induced factor 2 (Tgif2) as an essential direct miR-34a target that is pro-osteoclastogenic. Tgif2 deletion reduces bone resorption and abolishes miR-34a regulation. Together, using mouse genetic, pharmacological and disease models, we reveal miR-34a as a key osteoclast suppressor and a potential therapeutic strategy to confer skeletal protection and ameliorate bone metastasis of cancers.

Wnt/β-catenin signaling is a critical regulator of skeletal physiology. However, previous studies have mainly focused on its roles in osteoblasts, while its specific function in osteoclasts is unknown. This is a clinically important question because neutralizing antibodies against Wnt antagonists are promising new drugs for bone diseases. Here, we show that in osteoclastogenesis, β-catenin is induced during the macrophage colony-stimulating factor (M-CSF)-mediated quiescence-to-proliferation switch but suppressed during the RANKL-mediated proliferation-to-differentiation switch. Genetically, β-catenin deletion blocks osteoclast precursor proliferation, while β-catenin constitutive activation sustains proliferation but prevents osteoclast differentiation, both causing osteopetrosis. In contrast, β-catenin heterozygosity enhances osteoclast differentiation, causing osteoporosis. Biochemically, Wnt activation attenuates whereas Wnt inhibition stimulates osteoclastogenesis. Mechanistically, β-catenin activation increases GATA2/Evi1 expression but abolishes RANKL-induced c-Jun phosphorylation. Therefore, β-catenin exerts a pivotal biphasic and dosage-dependent regulation of osteoclastogenesis. Importantly, these findings suggest that Wnt activation is a more effective treatment for skeletal fragility than previously recognized that confers dual anabolic and anti-catabolic benefits.