Abstract
Heterotopic ossification (HO) represents a common problem after tendon injury with no effective treatment yet being developed. Tenomodulin (Tnmd), the best-known mature marker for tendon lineage cells, has important effects in tendon tissue aging and function. We have reported that loss of Tnmd leads to inferior early tendon repair characterized by fibrovascular scaring and therefore hypothesized that its lack will persistently cause deficient repair during later stages. Tnmd knockout (Tnmd−/−) and wild-type (WT) animals were subjected to complete Achilles tendon surgical transection followed by end-to-end suture. Lineage tracing revealed a reduction in tendon-lineage cells marked by ScleraxisGFP, but an increase in alpha smooth muscle actin myofibroblasts in Tnmd−/− tendon scars. At the proliferative stage, more pro-inflammatory M1 macrophages and larger collagen II cartilaginous template were detected in this group. At the remodeling stage, histological scoring revealed lower repair quality in the injured Tnmd−/− tendons, which was coupled with higher HO quantified by micro-CT. Tendon biomechanical properties were compromised in both groups upon injury, however we identified an abnormal stiffening of non-injured Tnmd−/− tendons, which possessed higher static and dynamic E-moduli. Pathologically thicker and abnormally shaped collagen fibrils were observed by TEM in Tnmd−/− tendons and this, together with augmented HO, resulted in diminished running capacity of Tnmd−/− mice. These novel findings demonstrate that Tnmd plays a protecting role against trauma-induced endochondral HO and can inspire the generation of novel therapeutics to accelerate repair.
Highlights
Heterotopic ossification (HO) is the process of ectopic cartilage formation followed by endochondral ossification of soft tissues such as tendons [1, 2]
Tnmd−/− scars harbor significantly higher number of αSMA+ cells and lower number of tendon-specific ScxGFP+ cells during early and late tendon healing Since ScxGFP+ and αSMA+ cells have been implicated as crucial players in the tendon repair process, we first investigated their abundance by lineage tracing at day 8, 21 and 100 post-injury
At day 100, ScxGFP+ and αSMA+ cells were present in the scar regions that appeared to be ossified (Fig. 1G–H2) and the percentage of ScxGFP+ cells was significantly lower in the Tnmd−/− tendons compared to WT (Fig. 1C), whilst the very low abundant αSMA+ cells were comparable between the groups (Fig. 1D)
Summary
Heterotopic ossification (HO) is the process of ectopic cartilage formation followed by endochondral ossification of soft tissues such as tendons [1, 2]. These data demonstrate that loss of Tnmd results in myofibroblast-enriched early scar tissue and significantly lower content of tendon lineage ScxGFP+ cells during early and late repair stages.
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