Emerging immune therapy, such as with the anti–programmed cell death–1 (anti–PD-1) monoclonal antibody nivolumab, has shown efficacy in tumor suppression. Patients with terminal cancer suffer from cancer pain as a result of bone metastasis and bone destruction, but how PD-1 blockade affects bone cancer pain remains unknown. Here, we report that mice lacking Pdcd1 (Pd1^−/−) demonstrated remarkable protection against bone destruction induced by femoral inoculation of Lewis lung cancer cells. Compared with WT mice, Pd1^−/− mice exhibited increased baseline pain sensitivity, but the development of bone cancer pain was compromised in Pd1^−/− mice. Consistently, these beneficial effects in Pd1^−/− mice were recapitulated by repeated i.v. applications of nivolumab in WT mice, even though nivolumab initially increased mechanical and thermal pain. Notably, PD-1 deficiency or nivolumab treatment inhibited osteoclastogenesis without altering tumor burden. PD-L1 and CCL2 are upregulated within the local tumor microenvironment, and PD-L1 promoted RANKL-induced osteoclastogenesis through JNK activation and CCL2 secretion. Bone cancer upregulated CCR2 in primary sensory neurons, and CCR2 antagonism effectively reduced bone cancer pain. Our findings suggest that, despite a transient increase in pain sensitivity following each treatment, anti–PD-1 immunotherapy could produce long-term benefits in preventing bone destruction and alleviating bone cancer pain by suppressing osteoclastogenesis.

The maintenance of muscle homeostasis is vital for life and health. Skeletal muscle atrophy not only seriously reduces people’s quality of life and increases morbidity and mortality, but also causes a huge socioeconomic burden. To date, no effective treatment has been developed for skeletal muscle atrophy owing to an incomplete understanding of its molecular mechanisms. Exercise therapy is the most effective treatment for skeletal muscle atrophy. Unfortunately, it is not suitable for all patients, such as fractured patients and bedridden patients with nerve damage. Therefore, understanding the molecular mechanism of skeletal muscle atrophy is crucial for developing new therapies for skeletal muscle atrophy. In this review, PubMed was systematically screened for articles that appeared in the past 5 years about potential therapeutic strategies for skeletal muscle atrophy. Herein, we summarize the roles of inflammation, oxidative stress, ubiquitin-proteasome system, autophagic-lysosomal pathway, caspases, and calpains in skeletal muscle atrophy and systematically expound the potential drug targets and therapeutic progress against skeletal muscle atrophy. This review focuses on current treatments and strategies for skeletal muscle atrophy, including drug treatment (active substances of traditional Chinese medicine, chemical drugs, antioxidants, enzyme and enzyme inhibitors, hormone drugs, etc.), gene therapy, stem cell and exosome therapy (muscle-derived stem cells, non-myogenic stem cells, and exosomes), cytokine therapy, physical therapy (electroacupuncture, electrical stimulation, optogenetic technology, heat therapy, and low-level laser therapy), nutrition support (protein, essential amino acids, creatine, β-hydroxy-β-methylbutyrate, and vitamin D), and other therapies (biomaterial adjuvant therapy, intestinal microbial regulation, and oxygen supplementation). Considering many treatments have been developed for skeletal muscle atrophy, we propose a combination of proper treatments for individual needs, which may yield better treatment outcomes.

A favorable microenvironment plays an important role in nerve regeneration. Extracellular matrix (ECM) derived from cultured cells or natural tissues can facilitate nerve regeneration in the presence of various microenvironmental cues, including biochemical, spatial, and biomechanical factors. This study, through proteomics and three-dimensional image analysis, determines that the components and spatial organization of the ECM secreted by bone marrow mesenchymal cells (BMSCs) are more similar to acellular nerves than those of the ECMs derived from Schwann cells (SCs), skin-derived precursor Schwann cells (SKP-SCs), or fibroblasts (FBs). ECM-modified nerve grafts (ECM-NGs) are engineered by co-cultivating BMSCs, SCs, FBs, SKP-SCs with well-designed nerve grafts used to bridge nerve defects. BMSC-ECM-NGs exhibit the most promising nerve repair properties based on the histology, neurophysiology, and behavioral analyses. The regeneration microenvironment formed by the ECM-NGs is also characterized by proteomics, and the advantages of BMSC-ECM-NGs are evidenced by the enhanced expression of factors related to neural regeneration and reduced immune response. Together, these findings indicate that BMSC-derived ECMs create a more superior microenvironment for nerve regeneration than that by the other ECMs and may, therefore, represent a potential alternative for the clinical repair of peripheral nerve defects.

Extracellular/acellular matrix-containing neural scaffolds represent a promising design of a tissue engineered nerve graft (TENG) for peripheral nerve repair. In this study, we engineered a composite neural scaffold by culturing dog bone marrow mesenchymal stem cells (BMSCs) onto the surface of a chitosan/silk fibroin-based scaffold and then exposing the cell culture to decellularization to deposit acellular matrix (ACM) coatings on the scaffold. This natural biomaterial-based, cell-derived ACM-coated neural scaffold, as a novel nerve graft, was used to bridge a 60 mm long nerve gap in a dog sciatic nerve. At 12 months after grafting, behavioral, functional, and histological evaluation indicated that our developed neural scaffold achieved satisfactory regenerative outcomes, which were very close to those achieved by autologous nerve grafts, the accepted golden standard for peripheral nerve repair. Moreover, additional therapeutic benefits produced by the modification of a neural scaffold with BMSC-derived ACM may be associated with the unique neural activity of the ACM, as evidenced by in vitro experimental findings that the ACM significantly enhanced axonal regrowth and Schwann cell proliferation. Our results will provide a further experimental basis for the translation of ACM-containing neural scaffolds into the clinic.