Tendon mineralization is progressive and associated with deterioration of tendon biomechanical properties, and requires BMP-Smad signaling in the mouse Achilles tendon injury model

Abstract

Ectopic tendon mineralization can develop following tendon rupture or trauma surgery. The pathogenesis of ectopic tendon mineralization and its clinical impact have not been fully elucidated yet. In this study, we utilized a mouse Achilles tendon injury model to determine whether ectopic tendon mineralization alters the biomechanical properties of the tendon and whether BMP signaling is involved in this condition. A complete transverse incision was made at the midpoint of the right Achilles tendon in 8-week-old CD1 mice and the gap was left open. Ectopic cartilaginous mass formation was found in the injured tendon by 4 weeks post-surgery and ectopic mineralization was detected at 8–10 weeks post-surgery. Ectopic mineralization grew over time and volume of the mineralized materials of 25-weeks samples was about 2.5 fold bigger than that of 10-weeks samples, indicating that injury-induced ectopic tendon mineralization is progressive. In vitro mechanical testing showed that max force, max stress and mid-substance modulus in the 25-weeks samples were significantly lower than the 10-weeks samples. We observed substantial increases in expression of bone morphogenetic protein family genes in injured tendons 1 week post-surgery. Immunohistochemical analysis showed that phosphorylation of both Smad1 and Smad3 were highly increased in injured tendons as early as 1 week post-injury and remained high in ectopic chondrogenic lesions 4 weeks post-injury. Treatment with the BMP receptor kinase inhibitor (LDN193189) significantly inhibited injury-induced tendon mineralization. These findings indicate that injury-induced ectopic tendon mineralization is progressive, involves BMP signaling and associated with deterioration of tendon biomechanical properties.

The metalloproteinase-proteoglycans ADAMTS7 and ADAMTS12 provide an innate, tendon-specific protective mechanism against heterotopic ossification

“…Bgn -/0 Fmod -/mice have more tendon progenitor cells and reduction of biglycan and fibromodulin upregulated BMP signaling (43). BMP signaling inhibits tendon formation during development (44), whereas increased BMP signaling is associated with HO (45). Adamts7 -/-Adamts12 -/mice had reduced, rather than absent biglycan and fibromodulin, which could explain why the observed anomalies were not as severe as in Bgn -/0 Fmod -/mice, and like them, showed upregulated BMP signaling at sites of HO.…”

Identification of differentially expressed micro-RNA in rotator cuff tendinopathy

“…While there have been no reports describing association of miRNA and BMP levels within a tendon model, miR has been shown to have regulatory control over BMP in other disease states. This is significant as increased expression of BMP has been shown to impair the development of tendon stem progenitor cells into tenocytes 9,38 , a critical cellular component of native tendon tissue. Icli et al, investigating angiogenesis from endothelial cells, reported that systemic intravenous administration of an miR-26a inhibitor increased BMP expression and rapidly induced robust angiogenesis 10 .…”

Effects of hydrogen peroxide on biological characteristics and osteoinductivity of decellularized and demineralized bone matrices

“…Moreover, BMP‐2 is the only common link between the various forms of heterotopic ossification (HO) . Nevertheless, HO that has been extensively observed in ruptured tendons, degenerative tendons/ligaments, or tendinitis is associated with the limited morbidity, pain, dysfunction, and weakened biomechanics of tendons/ligaments . Accordingly, mitigating or eliminating the risk of HO is essential to DBMs for the application of soft connective tissues regeneration.…”

“…16 Nevertheless, HO that has been extensively observed in ruptured tendons, degenerative tendons/ligaments, or tendinitis is associated with the limited morbidity, pain, dysfunction, and weakened biomechanics of tendons/ligaments. [17][18][19] Accordingly, mitigating or eliminating the risk of HO is essential to DBMs for the application of soft connective tissues regeneration. The targeted inhibition of local osteoinductive factors and signaling pathways should be the future strategies for HO prevention.…”