Heterotopic mineralization (ossification or calcification) in tendinopathy or following surgical tendon trauma

O'Brien, E. J. O.; Frank, Cyril B.; Shrive, Nigel G.; Hallgrímsson, Benedikt; Hart, David A.

doi:10.1111/j.1365-2613.2012.00829.x

Cited by 106 publications

(125 citation statements)

References 93 publications

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“…In human, heterotopic ossification is a substantial medical problem because it is associated with pain and dysfunction (28). In systemic heterotopic ossification, a fibrodysplasia ossificans progressiva-like phenotype (29) and ossification of the posterior longitudinal ligament of the spine (30) are important hereditary diseases, although these ossifications occur only several years after birth.…”

Section: Discussionmentioning

confidence: 99%

“…The upregulation of BMP pathway-related genes in the Achilles tendon of Mkx −/− rats suggests that Mkx regulates the BMP pathway. Mechanical stress affects tendon development before and after birth (40), and excessive mechanical stress can lead to ossification of the tendon (28,41). It is also reported that mechanical strain promotes the differentiation of MSCs into tenocytes in vitro (21,42).…”

Section: Discussionmentioning

confidence: 99%

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Gene targeting of the transcription factor Mohawk in rats causes heterotopic ossification of Achilles tendon via failed tenogenesis

Suzuki

Ito

Shirakawa

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

105

113

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Cell-based or pharmacological approaches for promoting tendon repair are currently not available because the molecular mechanisms of tendon development and healing are not well understood. Although analysis of knockout mice provides many critical insights, small animals such as mice have some limitations. In particular, precise physiological examination for mechanical load and the ability to obtain a sufficient number of primary tendon cells for molecular biology studies are challenging using mice. Here, we generated Mohawk (Mkx) −/− rats by using CRISPR/Cas9, which showed not only systemic hypoplasia of tendons similar to Mkx −/− mice, but also earlier heterotopic ossification of the Achilles tendon compared with Mkx −/− mice. Analysis of tendon-derived cells (TDCs) revealed that Mkx deficiency accelerated chondrogenic and osteogenic differentiation, whereas Mkx overexpression suppressed chondrogenic, osteogenic, and adipogenic differentiation. Furthermore, mechanical stretch stimulation of Mkx −/− TDCs led to chondrogenic differentiation, whereas the same stimulation in Mkx +/+ TDCs led to formation of tenocytes. ChIP-seq of Mkx overexpressing TDCs revealed significant peaks in tenogenic-related genes, such as collagen type (Col)1a1 and Col3a1, and chondrogenic differentiation-related genes, such as SRY-box (Sox)5, Sox6, and Sox9. Our results demonstrate that Mkx has a dual role, including accelerating tendon differentiation and preventing chondrogenic/ osteogenic differentiation. This molecular network of Mkx provides a basis for tendon physiology and tissue engineering.Achilles tendon ossification T endons play a critical role in the musculoskeletal system by connecting muscle to bone to transmit mechanical loads and enable movement. Tendon injuries and damage are repaired slowly and incompletely because of poor intrinsic healing capacity, which in part results from tissue hypocellularity and hypovascularity (1). Even after surgical tendon repair, a standard treatment for tendon rupture, clinical outcomes are not satisfactory because of recurrent rupture or adhesions (2). To develop cell-based or pharmacological approaches for promoting tendon repair, the molecular mechanism of tendon development and regeneration must be determined; however, the key genome network for tendon differentiation and homeostasis has not been well characterized.We, along with other researchers, recently reported the tendon-specific expression and functions of the transcription factor Mohawk (Mkx), which regulates tendon-related gene expression (3, 4). Mkx knockout mice showed general tendon hypoplasia (5, 6), suggesting that Mkx plays an important role during tendon development. Moreover, overexpression of Mkx in mesenchymal stem cells (MSC) elevates tendon-related markers, and transplantation of these cells increases the diameter of collagen fibers in tendons (7,8), suggesting the potential application of Mkx in cell therapy for tendon injury.Although the results from analysis of Mkx knockout mice have provided critical informatio...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Gene targeting of the transcription factor Mohawk in rats causes heterotopic ossification of Achilles tendon via failed tenogenesis

Suzuki

Ito

Shirakawa

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

105

113

View full text Add to dashboard Cite

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“…The linear appearance and the location of soft tissue mineralisation in our elephants suggest that the digital flexor tendons are the affected structures. Mineralisation of the deep digital flexor tendon in horses has been observed as a response to chronic injury (Dyson, 2003b), and general mineralisation has been described as a feature of tendinopathy (tendon disease arising from overuse) and following trauma in other species (O’Brien et al, 2012). The magnitude of load experienced by structures may be a factor (especially in OA and remodelling, which both increase with increasing age and therefore presumably body weight), as might the type of loading; e.g., altered locomotion or long periods of standing.…”

Section: Discussionmentioning

confidence: 99%

Skeletal pathology and variable anatomy in elephant feet assessed using computed tomography

Regnault

Dixon

Warren-Smith

et al. 2017

PeerJ

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Foot problems are a major cause of morbidity and mortality in elephants, but are underreported due to difficulties in diagnosis, particularly of conditions affecting the bones and internal structures. Here we evaluate post-mortem computer tomographic (CT) scans of 52 feet from 21 elephants (seven African Loxodonta africana and 14 Asian Elephas maximus), describing both pathology and variant anatomy (including the appearance of phalangeal and sesamoid bones) that could be mistaken for disease. We found all the elephants in our study to have pathology of some type in at least one foot. The most common pathological changes observed were bone remodelling, enthesopathy, osseous cyst-like lesions, and osteoarthritis, with soft tissue mineralisation, osteitis, infectious osteoarthriti, subluxation, fracture and enostoses observed less frequently. Most feet had multiple categories of pathological change (81% with two or more diagnoses, versus 10% with a single diagnosis, and 9% without significant pathology). Much of the pathological change was focused over the middle/lateral digits, which bear most weight and experience high peak pressures during walking. We found remodelling and osteoarthritis to be correlated with increasing age, more enthesopathy in Asian elephants, and more cyst-like lesions in females. We also observed multipartite, missing and misshapen phalanges as common and apparently incidental findings. The proximal (paired) sesamoids can appear fused or absent, and the predigits (radial/tibial sesamoids) can be variably ossified, though are significantly more ossified in Asian elephants. Our study reinforces the need for regular examination and radiography of elephant feet to monitor for pathology and as a tool for improving welfare.

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“…Significance of Dcn and Mkx by IL-1β needs to be further investigated. Tendon mineralization can be found as a result of tendon injuries or a feature of tendinopathy [28, 29]. Previous studies reported that mineralization was found in 14–62% of cases following percutaneous or open repair of the Achilles tendon [30] and is thought to be a cause of pain and tendon weakness [31, 32].…”

Section: Discussionmentioning

confidence: 99%

IL-1β irreversibly inhibits tenogenic differentiation and alters metabolism in injured tendon-derived progenitor cells in vitro

Zhang

Asai

et al. 2015

Biochemical and Biophysical Research Communications

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Tendon injuries are common, and the damaged tendon often turns into scar tissue and never completely regains the original biomechanical properties. Previous studies have reported that the mRNA levels of inflammatory cytokines such as IL-1β are remarkably up-regulated in injured tendons. To examine how IL-1β impacts tendon repair process, we isolated the injured tendon-derived progenitor cells (inTPCs) from mouse injured Achilles tendons and studied the effects of IL-1β on the inTPCs in vitro. IL-1β treatment strongly reduced expression of tendon cell markers such as scleraxis and tenomodulin, and also down-regulated gene expression of collagen 1, collagen 3, biglycan and fibromodulin in inTPCs. Interestingly, IL-1β stimulated lactate production with increases in hexokinase II and lactate dehydrogenase expression and a decrease in pyruvate dehydrogenase. Inhibition of lactate production restored IL-1β-induced down-regulation of collagen1 and scleraxis expression. Furthermore, IL-1β significantly inhibited adipogenic, chondrogenic and osteogenic differentiation of inTPCs. Interestingly, inhibition of tenogenic and adipogenic differentiation was not recovered after removal of IL-1β while chondrogenic and osteogenic differentiation abilities were not affected. These findings indicate that IL-1β strongly and irreversibly impairs tenogenic potential and alters glucose metabolism in tendon progenitors appearing in injured tendons. Inhibition of IL-1β may be beneficial for maintaining function of tendon progenitor cells during the tendon repair process.

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Heterotopic mineralization (ossification or calcification) in tendinopathy or following surgical tendon trauma

Cited by 106 publications

References 93 publications

Gene targeting of the transcription factor Mohawk in rats causes heterotopic ossification of Achilles tendon via failed tenogenesis

Gene targeting of the transcription factor Mohawk in rats causes heterotopic ossification of Achilles tendon via failed tenogenesis

Skeletal pathology and variable anatomy in elephant feet assessed using computed tomography

IL-1β irreversibly inhibits tenogenic differentiation and alters metabolism in injured tendon-derived progenitor cells in vitro

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