Whether sensory nerve can sense bone density or metabolic activity to control bone homeostasis is unknown. Here we found prostaglandin E2 (PGE2) secreted by osteoblastic cells activates PGE2 receptor 4 (EP4) in sensory nerves to regulate bone formation by inhibiting sympathetic activity through the central nervous system. PGE2 secreted by osteoblasts increases when bone density decreases as demonstrated in osteoporotic animal models. Ablation of sensory nerves erodes the skeletal integrity. Specifically, knockout of the EP4 gene in the sensory nerves or cyclooxygenase-2 (COX2) in the osteoblastic cells significantly reduces bone volume in adult mice. Sympathetic tone is increased in sensory denervation models, and propranolol, a β2-adrenergic antagonist, rescues bone loss. Furthermore, injection of SW033291, a small molecule to increase PGE2 level locally, significantly boostes bone formation, whereas the effect is obstructed in EP4 knockout mice. Thus, we show that PGE2 mediates sensory nerve to control bone homeostasis and promote regeneration.

Since the proposal of Paul Ehrlich’s magic bullet concept over 100 years ago, tremendous advances have occurred in targeted therapy. From the initial selective antibody, antitoxin to targeted drug delivery that emerged in the past decades, more precise therapeutic efficacy is realized in specific pathological sites of clinical diseases. As a highly pyknotic mineralized tissue with lessened blood flow, bone is characterized by a complex remodeling and homeostatic regulation mechanism, which makes drug therapy for skeletal diseases more challenging than other tissues. Bone-targeted therapy has been considered a promising therapeutic approach for handling such drawbacks. With the deepening understanding of bone biology, improvements in some established bone-targeted drugs and novel therapeutic targets for drugs and deliveries have emerged on the horizon. In this review, we provide a panoramic summary of recent advances in therapeutic strategies based on bone targeting. We highlight targeting strategies based on bone structure and remodeling biology. For bone-targeted therapeutic agents, in addition to improvements of the classic denosumab, romosozumab, and PTH1R ligands, potential regulation of the remodeling process targeting other key membrane expressions, cellular crosstalk, and gene expression, of all bone cells has been exploited. For bone-targeted drug delivery, different delivery strategies targeting bone matrix, bone marrow, and specific bone cells are summarized with a comparison between different targeting ligands. Ultimately, this review will summarize recent advances in the clinical translation of bone-targeted therapies and provide a perspective on the challenges for the application of bone-targeted therapy in the clinic and future trends in this area.

Myocardial infarction (MI) is a major form of heart disease that leads to immediate cardiomyocyte death due to ischemia and eventually fibrosis and scar formation and further dysfunction of myocardium and heart failure. Extracellular matrix (ECM) production and tissue repair is conducted by myofibroblasts, which are formed from the normal quiescent cardiac fibroblasts following transformational changes, through the active participation of transforming growth factor β (TGFβ) and its signaling pathways. TGFβ appears to be a ‘Master of all trades’, with respect to cardiac fibrosis, as it can promote cardiomyocyte apoptosis and cardiac hypertrophy. TGFβ signaling involves its binding to TGFβ receptor type II (TGFβRII), which recruits TGFβ receptor type I (TGFβRI), which are also known as activin receptor-like kinase (ALK) in five different isoforms. In canonical signaling pathways, ALK5 activates Smads 2 and 3, and ALK1 activates Smads 1 and 5. These pairs of Smads form a corresponding complex and then bind to Smad 4, to translocate into the nucleus, where transcriptional reprogramming is carried out to promote myofibroblast formation and ECM production, eventually leading to cardiac fibrosis. TGFβ levels are elevated in MI, thereby aggravating the myocardial injury further. Several microRNAs are involved in the regulation of TGFβ signaling at different steps, affecting different components. Therapeutic targeting of TGFβ signaling at ALK1-5 receptor activity level has met with limited success and extensive research is needed to develop therapies based on the components of TGFβ signaling pathway, for instance cardiac dysfunction and heart failure.

Increased bone resorption by osteoclasts after estrogen deficiency is the main cause of postmenopausal osteoporosis. TET2 (tet methylcytosine dioxygenase 2) is a DNA demethylase that regulates cellular function and differentiation potential. Macroautophagy/autophagy maintains cellular homeostasis by recycling unnecessary and damaged organelles. This study revealed that TET2 promoted bone loss in oophorectomized (OVX) mice and that TET2 promoted osteoclast differentiation by regulating autophagy. Tet2 knockdown inhibited autophagy and osteoclast differentiation in vitro. Mechanistically, Tet2 knockdown increased BCL2 (B cell leukemia/lymphoma 2) expression and BCL2 exhibited increased binding to BECN1 and negatively regulated autophagy. Small interfering RNA specific to Bcl2 interfered with BCL2 expression in Tet2-knockdown bone marrow cells/precursors, partially reversing autophagy dysregulation and promoting osteoclast differentiation. Moreover, the LV-shTet2 lentivirus prevented bone loss in OVX mice. In summary, our findings provide evidence that TET2 promotes osteoclast differentiation by inhibiting BCL2 expression and positively regulating BECN1-dependent autophagy. Abbreviations: ACP5/TRAP: acid phosphatase 5, tartrate resistant; ATP6V0D2: ATPase, H+ transporting, lysosomal V0 subunit D2; BCL2: B cell leukemia/lymphoma 2; BECN1: beclin 1, autophagy related; BMs: bone marrow cells; CTSK: cathepsin K; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MMP9: matrix metallopeptidase 9; OVX: oophorectomy; RUNX1: runt related transcription factor 1; SOCS3: suppressor of cytokine signaling 3; SPI1/PU.1: Spi-1 proto-oncogene; TNFSF11/RANKL: tumor necrosis factor (ligand) superfamily, member 11; TET2: tet methylcytosine dioxygenase 2.