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Targeted pathological collagen delivery of sustained-release rapamycin to prevent heterotopic ossification.

ABSTRACT: Heterotopic ossification (HO) in connective tissues like tendons and ligaments severely damages tissue structure. The pathogenesis of HO remains unclear but may involve mTOR. The results presented here indicate that tendon stem/progenitor cells do not undergo osteochondrogenic differentiation when mTOR signaling is inactivated by gene knockout or rapamycin (RAPA) treatment. Meanwhile, it is necessary to deliver RAPA to the injured sites and avoid disturbing the normal tendon. A RAPA delivery system, developed using collagen hybrid peptide (CHP) to modify the surface of poly(lactic-co-glycolic acid) (PLGA) nanoparticles, targeted RAPA specifically to pathological tendon collagen. The CHP-PLGA-RAPA nanoparticles showed excellent pathological collagen affinity, sustained-release ability, and bioactivity. In a mouse model of tendon HO, CHP-PLGA-RAPA nanoparticles specifically bound to pathological tendon and strongly suppressed HO progression. The mTOR signaling pathway appears to be a viable therapeutic target for tendon HO, and CHP-PLGA nanoparticles may be valuable for the treatment of tendon-related diseases.

SUBMITTER: Chen Y

PROVIDER: S-EPMC7239699 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Targeted pathological collagen delivery of sustained-release rapamycin to prevent heterotopic ossification.

Chen Yangwu Y Shen Weiliang W Tang Chenqi C Huang Jiayun J Fan Chunmei C Yin Zi Z Hu Yejun Y Chen Weishan W Ouyang Hongwei H Zhou Yiting Y Mao Zhengwei Z Chen Xiao X

Science advances 20200429 18

Heterotopic ossification (HO) in connective tissues like tendons and ligaments severely damages tissue structure. The pathogenesis of HO remains unclear but may involve mTOR. The results presented here indicate that tendon stem/progenitor cells do not undergo osteochondrogenic differentiation when mTOR signaling is inactivated by gene knockout or rapamycin (RAPA) treatment. Meanwhile, it is necessary to deliver RAPA to the injured sites and avoid disturbing the normal tendon. A RAPA delivery sys ...[more]

PMID: 32494667

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Project description:BackgroundTraumatic heterotopic ossification (THO) is a devastating sequela following traumatic injuries and orthopedic surgeries. To date, the exact molecular mechanism of THO formation is still unclear, which hinders the development of effective treatments. The process of THO formation is believed to recapitulate a series of spatiotemporal cellular and signaling events that occur during skeletal development. The Notch signaling pathway is a critical genetic regulator in embryological bone development and fracture healing. However, few data are available concerning whether Notch signaling regulates THO development and maturation.MethodsWe firstly detected the expressions of Notch target genes in both mouse and human THO samples with quantitative RT-PCR and immunohistochemistry (IHC). Then, tissue-resident mesenchymal progenitor cells (TMPCs) were isolated, and the abilities of the proliferation and osteogenic and chondrogenic differentiation of TMPCs were examined under the intervention of the gamma-secretase inhibitor-DAPT at different time points. Finally, DAPT was also administrated in THO mice by burn and Achilles tenotomy injury, and ectopic cartilage and bone formation were monitored by histology and micro-CT.ResultsSeveral Notch target genes were upregulated in both mouse and human THO tissues. Sustained Notch signaling inhibition by DAPT reduced proliferation, osteogenic and chondrogenic differentiation of TMPCs in a time-dependent manner. Moreover, DAPT administration within 3 weeks could inhibit ectopic cartilage and bone formation in a mouse THO model without affecting the total body bone mass.ConclusionsThe Notch signaling serves as an important therapeutic target during THO formation. And sustained gamma-secretase inhibition by DAPT has great potential in repressing chondrogenic and osteogenic differentiation of TMPCs, as well as inhibited ectopic cartilage and bone formation in vivo.The translational potential of this articleSustained Notch inhibition via systemic DAPT (or other similar gamma-secretase inhibitors) administration has promising clinical utility for inhibiting THO formation, providing new insight into THO prophylaxis and treatment.

Project description:Heterotopic ossification (HO) is the formation of abnormal mature lamellar bone in extra-skeletal sites, including soft tissues and joints, which result in high rates of disability. The understanding of the mechanism of HO is insufficient. The aim of this study was to explore biomarkers and pathological processes in HO+ samples. The gene expression profile GSE94683 was downloaded from the Gene Expression Omnibus database. Sixteen samples from nine HO- and seven HO+ subjects were analyzed. After data preprocessing, 3,529 genes were obtained for weighted gene co-expression network analysis. Highly correlated genes were divided into 13 modules. Finally, the cyan and purple modules were selected for further study. Gene ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment indicated that the cyan module was enriched in a variety of components, including protein binding, membrane, nucleoplasm, cytosol, poly(A) RNA binding, biosynthesis of antibiotics, carbon metabolism, endocytosis, citrate cycle, and metabolic pathways. In addition, the purple module was enriched in cytosol, mitochondrion, protein binding, structural constituent of ribosome, rRNA processing, oxidative phosphorylation, ribosome, and non-alcoholic fatty liver disease. Finally, 10 hub genes in the cyan module [actin related protein 3 (ACTR3), ADP ribosylation factor 4 (ARF4), progesterone receptor membrane component 1 (PGRMC1), ribosomal protein S23 (RPS23), mannose-6-phosphate receptor (M6PR), WD repeat domain 12 (WDR12), synaptosome associated protein 23 (SNAP23), actin related protein 2 (ACTR2), siah E3 ubiquitin protein ligase 1 (SIAH1), and glomulin (GLMN)] and 2 hub genes in the purple module [proteasome 20S subunit alpha 3 (PSMA3) and ribosomal protein S27 like (RPS27L)] were identified. Hub genes were validated through quantitative real-time polymerase chain reaction. In summary, 12 hub genes were identified in two modules that were associated with HO. These hub genes could provide new biomarkers, therapeutic ideas, and targets in HO.

Dataset Information

Targeted pathological collagen delivery of sustained-release rapamycin to prevent heterotopic ossification.

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Targeted pathological collagen delivery of sustained-release rapamycin to prevent heterotopic ossification.

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