Age-related Impairment of Implant Osseointegration is Associated with Immune Activation and Suppression of Angiogenic, Notch, and Wnt Pathways

Abstract

The number of total joint replacements (TJRs) in the United States is increasing annually. Cementless implants are intended to improve upon traditional cemented implants by allowing bone growth directly on the surface to improve implant longevity. One major complication of TJR is implant loosening, which is related to deficient osseointegration in cementless TJRs. Although poor osseointegration in aged patients is typically attributed to decreased basal bone mass, little is known about the molecular pathways that compromise the growth of bone onto porous titanium implants. To identify the pathways important for osseointegration that are compromised by aging, we developed an approach for transcriptomic profiling of peri-implant tissue in young and aged mice using our murine model of osseointegration. Based on previous findings of changes of bone quality associated with aging, we hypothesized that aged mice have impaired activation of bone anabolic pathways at the bone-implant interface. We found that pathways most significantly downregulated in aged mice relative to young mice are related to angiogenic, Notch and Wnt signaling. Downregulation of these pathways is associated with markedly increased expression of inflammatory and immune genes at the bone-implant interface in aged mice. These results identify osseointegration pathways affected by aging and suggest that an increased inflammatory response in aged mice may compromise peri-implant bone healing. Targeting the Notch and Wnt pathways, promoting angiogenesis, or modulating the immune response at the peri-implant site may enhance osseointegration and improve the outcome of joint replacement in older patients.

Tmem100- and Acta2-Lineage Cells Contribute to Implant Osseointegration in a Mouse Model

“…We reevaluated a bulk RNA‐seq data set that we previously generated to determine transcripts that significantly differed between peri‐implant tissue and control cancellous bone tissue. ( 14 ) Briefly, tibial implants were inserted into 16‐week‐old C57/BL6 female mice and removed 7 days later. We found significant differences in the abundances of 1173 transcripts (false discovery rate [FDR] < 0.05, fold change > 2), with 310 enriched in peri‐implant tissue compared with cancellous bone (Supplemental Table S1).…”

“…5). We also compared our single‐cell RNA‐seq findings to the bulk RNA‐seq data set ( 14 ) that helped us identify Acta2 as a marker for peri‐implant cells: We hypothesized that the bulk transcriptome of peri‐implant cells would be enriched for transcripts that distinguish Pdgfra + and Ly6a + cells from osteoblasts. We, therefore, used the FindMarkers function to identify differentially expressed transcripts between clusters #0 and #6.…”