The bone resorbing osteoclasts significantly contribute to osteoporosis and cancer bone metastases1-3. MicroRNAs (miRNAs) play important roles in physiology and disease4,5, and present tremendous therapeutic potential6. Nonetheless, how miRNAs 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 down-regulated during osteoclast differentiation. Osteoclastic miR-34a over-expressing 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 Tgif2 (transforming growth factor-beta-induced factor 2) 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.

SUMMARY Fibroblast growth factor 21 (FGF21) promotes insulin sensitivity but causes bone loss. It elevates bone resorption by an undefined non-osteoclast-autonomous mechanism. We have detected a pro-osteoclastogenic activity in the hepatic secretome that is increased by FGF21, and largely attributed to insulin-like growth factor binding protein 1 (IGFBP1). Ex vivo osteoclast differentiation and in vivo bone resorption are both enhanced by recombinant IGFBP1 but suppressed by an IGFBP1-blocking antibody. Anti-IGFBP1 treatment attenuates ovariectomy-induced osteoporosis, and abolishes FGF21-induced bone loss while maintaining its insulin-sensitizing metabolic benefit. Mechanistically, IGFBP1 functions via its RGD domain to bind to its receptor integrin β1 on osteoclast precursors, thereby potentiating RANKL-stimulated Erk-phosphorylation and NFATc1 activation. Consequently, osteoclastic integrin β1 deletion confers resistance to the resorption-enhancing effects of both IGFBP1 and FGF21. Therefore, the hepatokine IGFBP1 is a critical liver-bone hormonal relay that promotes osteoclastogenesis and bone resorption, as well as an essential mediator of FGF21-induced bone loss.

Bone metastases are dejected consequences of many types of tumors including breast, prostate, lung, kidney and thyroid cancers. This complicated process begins with the successful tumor cell epithelial–mesenchymal transition, escape from the original site, and penetration into circulation. The homing of tumor cells to the bone depends on both tumor-intrinsic traits and various molecules supplied by the bone metastatic niche. The colonization and growth of cancer cells in the osseous environment, which awaken their dormancy to form micro- and macro-metastasis, involve an intricate interaction between the circulating tumor cells and local bone cells including osteoclasts, osteoblasts, adipocytes and macrophages. In this review, we discuss the most recent advances in the identification of new molecules and novel mechanisms during each step of bone metastasis that may serve as promising therapeutic targets.

SUMMARY Orexin neuropeptides promote arousal, appetite, reward, and energy expenditure. However, whether orexin affects bone mass accrual is unknown. Here we show that orexin functions centrally through orexin receptor 2 (OX2R) in the brain to enhance bone formation. OX2R-null mice exhibit low-bone-mass owing to elevated circulating leptin; whereas central administration of an OX2R-selective agonist augments bone mass. Conversely, orexin also functions peripherally through orexin receptor 1 (OX1R) in the bone to suppress bone formation. OX1R-null mice exhibit high-bone-mass owing to a mesenchymal stem cell differentiation shift from adipocyte to osteoblast that results from higher osseous ghrelin expression. The central action is dominant over the peripheral action because bone mass is reduced in orexin-null and OX1R2R-double-null mice but enhanced in orexin over-expressing transgenic mice. These findings reveal orexin as a critical rheostat of skeletal homeostasis that exerts a yin-yang dual regulation, and highlight orexin as a therapeutic target for osteoporosis.

XPC binds MDM2 ubiquitin ligase and participates in the MDM2-mediated p53 degradation. Furthermore, XPC overexpression stimulates p53 degradation following UV irradiation. Combined, the results suggest a key role of XPC in p53 degradation.