Current clinical approaches to osteoporosis primarily target osteoclast biology, overlooking the synergistic role of bone cells, immune cells, cytokines, and inorganic components in creating an abnormal osteoporotic microenvironment. Here, metal-polyDNA nanoparticles (Ca-polyCpG MDNs) composed of Ca ²⁺ and ultralong single-stranded CpG sequences were developed to reconstruct the osteoporotic microenvironment and suppress osteoporosis. Ca-polyCpG MDNs can neutralize osteoclast-secreted hydrogen ions, provide calcium repletion, promote remineralization, and repair bone defects. Besides, the immune-adjuvant polyCpG in MDNs could induce the secretion of osteoclastogenesis inhibitor interleukin-12 and reduce the expression of osteoclast function effector protein to inhibit osteoclast differentiation, further reducing osteoclast-mediated bone resorption. PPi ⁴⁻ generated during the rolling circle amplification reaction acts as bisphosphonate analog and enhances bone targeting of Ca-polyCpG MDNs. In ovariectomized mouse and rabbit models, Ca-polyCpG MDNs prevented bone resorption and promoted bone repair by restoring the osteoporotic microenvironment, providing valuable insights into osteoporosis therapy.

MicroRNAs (miRNAs) play critical roles in human cancers including osteosarcoma (OS). miR-92a has been found to be a cancer-related miRNA in many cancer types and it is upregulated in OS cell lines. However, the expression and biological function of miR-92a in OS have not been investigated. In this study, we showed that miR-92a expression was increased in OS tissues, and its high expression was correlated with clinical stage, T classification and histological differentiation. Furthermore, patients with high expression of miR-92a had a significantly poorer survival rate. Functionally, miR-92a overexpression promoted the proliferation and cell cycle progression, and inhibited apoptosis in MG-63 cells. While inhibition of miR-92a showed contrary effects with reduced proliferation, cell cycle arrest at G1 phase and increased apoptosis in U2OS cells. Moreover, we confirmed that miR-92a inhibition reversed the tumor growth of OS cells in nude mice. Phosphatase and tensin homolog (PTEN), a well-known tumor suppressor, was confirmed to be the direct downstream target of miR-92a in OS. Notably, miR-92a consequently regulated the expression of the downstream targets of PTEN/AKT signaling pathway including p-Akt(Ser473), mTOR, p-p27(Thr157) and p-MDM2(Ser166). Furthermore, PTEN knockdown abrogated the functional effects of miR-92a silencing on the proliferation, apoptosis and cell cycle progression in OS cells. Thus, miR-92a that exerts an oncogenic role by targeting PTEN/AKT pathway in OS potentially acts as a biomarker and drug-target.

Osteoporosis is a common metabolic bone disorder in the elderly population. The accumulation of bone microdamage is a critical factor of osteoporotic fracture. Neuropeptide Y (NPY) has been reported to regulated bone metabolism through Y1 receptor (Y1R). In this study the effects and mechanisms of Y1R antagonist on prevention for osteoporosis were characterized. In the clinical experiment, compared with osteoarthritis (OA), osteoporosis (OP) showed significant osteoporotic bone microstructure and accumulation of bone microdamage. NPY and Y1R immunoreactivity in bone were stronger in OP group, and were both correlated with bone volume fraction (BV/TV). In vivo experiment, Y1R antagonist significantly improved osteoporotic microstructure in the ovariectomized (OVX) rats. And Y1R antagonist promoted RUNX2, OPG and inhibit RANKL, MMP9 in bone marrow. In vitro cell culture experiment, NPY inhibited osteogenesis, elevated RANKL/OPG ratio and downregulated the expression of cAMP, p-PKAs and p-CREB in BMSCs, treated with Y1R antagonist or 8-Bromo-cAMP could inhibit the effects of NPY. Together, Y1R antagonist improved the bone microstructure and reduced bone microdamage in OVX rats. NPY-Y1R could inhibit osteoblast differentiation of BMSCs via cAMP/PKA/CREB pathway. Our findings highlight the regulation of NPY-Y1R in bone metabolism as a potential therapy strategy for the prevention of osteoporosis and osteoporotic fracture.

Rheumatoid arthritis (RA) and osteoarthritis (OA) are two major types of joint diseases that share multiple common symptoms. However, their pathological mechanism remains largely unknown. The aim of our study is to identify RA and OA related-genes and gain an insight into the underlying genetic basis of these diseases. We collected 11 whole genome-wide expression profiling datasets from RA and OA cohorts and performed a meta-analysis to comprehensively investigate their expression signatures. This method can avoid some pitfalls of single dataset analyses. We found that several biological pathways (i.e., the immunity, inflammation and apoptosis related pathways) are commonly involved in the development of both RA and OA. Whereas several other pathways (i.e., vasopressin-related pathway, regulation of autophagy, endocytosis, calcium transport and endoplasmic reticulum stress related pathways) present significant difference between RA and OA. This study provides novel insights into the molecular mechanisms underlying this disease, thereby aiding the diagnosis and treatment of the disease.