Scleraxis is required for maturation of tissue domains for proper integration of the musculoskeletal system

Yoshimoto, Yuki; Takimoto, Atsushi; Watanabe, Hidenobu; Hiraki, Yuji; Kondoh, Gen; Shukunami, Chisa

doi:10.1038/srep45010

Cited by 89 publications

(111 citation statements)

References 42 publications

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“…Tnmd expression was observed by us, along with other researchers, in tendons, ligaments, eyes, and CTC (Brandau et al, ; Kimura et al, ; Shukunami et al, ). In the vertebral column, previous studies have localized Tnmd gene expression to areas of the IVD (Minogue et al, ; Nakamichi et al, ), as well as Tnmd immunostainings carried out in neonate mice detected robust protein expression in the OAF (Yoshimoto et al, ). To further determine the precise distribution of Tnmd in the postnatal and adult IVD, we first performed immunolocalization studies on IVD tissues from WT mice at distinct stages of skeletal development ranging from newborn to 18 months of age.…”

Section: Resultsmentioning

confidence: 97%

Loss of tenomodulin expression is a risk factor for age‐related intervertebral disc degeneration

et al. 2020

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The intervertebral disc (IVD) degeneration is thought to be closely related to ingrowth of new blood vessels. However, the impact of anti‐angiogenic factors in the maintenance of IVD avascularity remains unknown. Tenomodulin (Tnmd) is a tendon/ligament‐specific marker and anti‐angiogenic factor with abundant expression in the IVD. It is still unclear whether Tnmd contributes to the maintenance of IVD homeostasis, acting to inhibit vascular ingrowth into this normally avascular tissue. Herein, we investigated whether IVD degeneration could be induced spontaneously by the absence of Tnmd. Our results showed that Tnmd was expressed in an age‐dependent manner primarily in the outer annulus fibrous (OAF) and it was downregulated at 6 months of age corresponding to the early IVD degeneration stage in mice. Tnmd knockout (Tnmd−/−) mice exhibited more rapid progression of age‐related IVD degeneration. These signs include smaller collagen fibril diameter, markedly lower compressive stiffness, reduced multiple IVD‐ and tendon/ligament‐related gene expression, induced angiogenesis, and macrophage infiltration in OAF, as well as more hypertrophic‐like chondrocytes in the nucleus pulposus. In addition, Tnmd and chondromodulin I (Chm1, the only homologous gene to Tnmd) double knockout (Tnmd−/−Chm1−/−) mice displayed not only accelerated IVD degeneration, but also ectopic bone formation of IVD. Lastly, the absence of Tnmd in OAF‐derived cells promoted p65 and matrix metalloproteinases upregulation, and increased migratory capacity of human umbilical vein endothelial cells. In sum, our data provide clear evidences that Tnmd acts as an angiogenic inhibitor in the IVD homeostasis and protects against age‐related IVD degeneration. Targeting Tnmd may represent a novel therapeutic strategy for attenuating age‐related IVD degeneration.

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Section: Resultsmentioning

confidence: 97%

Loss of tenomodulin expression is a risk factor for age‐related intervertebral disc degeneration

et al. 2020

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“…; Yoshimoto et al. ) and is involved in regulating Tnmd expression, which itself serves as tendon and tendon progenitor cell marker (Shukunami et al. ).…”

Section: Resultsmentioning

confidence: 99%

Potential biomarkers of the mature intervertebral disc identified at the single cell level

Kapper

Youngs

et al. 2018

Journal of Anatomy

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Intervertebral disc (IVD) degeneration and trauma is a major socio-economic burden and the focus of cell-based regenerative medicine approaches. Despite numerous ongoing clinical trials attempting to replace ailing IVD cells with mesenchymal stem cells, a solid understanding of the identity and nature of cells in a healthy mature IVD is still in need of refinement. Although anatomically simple, the IVD is comprised of heterogeneous cell populations. Therefore, methods involving cell pooling for RNA profiling could be misleading. Here, by using RNA in situ hybridization and z proportion test, we have identified potential novel biomarkers through single cell assessment. We quantified the proportion of RNA transcribing cells for 50 genetic loci in the outer annulus fibrosus (AF) and nucleus pulposus (NP) in coccygeal bovine discs isolated from tails of four skeletally mature animals. Our data reconfirm existing data and suggest 10 novel markers such as Lam1 and Thy1 in the outer AF and Gli1, Gli3, Noto, Scx, Ptprc, Sox2, Zscan10 and LOC101904175 in the NP, including pluripotency markers, that indicate stemness potential of IVD cells. These markers could be added to existing biomarker panels for cell type characterization. Furthermore, our data once more demonstrate heterogeneity in cells of the AF and NP, indicating the need for single cell assessment by methods such as RNA in situ hybridization. Our work refines the molecular identity of outer AF and NP cells, which can benefit future regenerative medicine and tissue engineering strategies in humans.

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“…Scleraxis appears to be important in embryonic tendon development, in part, by directing the expression of type I collagen, tenomodulin, and fibronectin (12,13,(31)(32)(33). Mechanical loading increases the expression of scleraxis, type I and III collagen, and tenomodulin in tendon (6,14,34,35), and our transcriptomic analyses demonstrated that expression of components or regulators of the ECM, including Col1a1, Mkx and Tnmd, were found to be reduced in the absence of scleraxis in whole tendons and in cultured tenocytes.…”

Section: Discussionmentioning

confidence: 53%

Scleraxis is required for the growth of adult tendons in response to mechanical loading

Gumucio

Schonk

Kharaz

et al. 2020

Preprint

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Scleraxis is a basic helix-loop-helix transcription factor that plays a central role in promoting tenocyte proliferation and matrix synthesis during embryonic tendon development.However, the role of scleraxis in the growth and adaptation of adult tendons is not known. We hypothesized that scleraxis is required for tendon growth in response to mechanical loading, and that scleraxis promotes the specification of progenitor cells into tenocytes. We conditionally deleted scleraxis in adult mice using a tamoxifen-inducible Cre-recombinase expressed from the Rosa26 locus (Scx Δ ), and then induced tendon growth in Scx + and Scx Δ adult mice via plantaris tendon mechanical overload. Compared to the wild type Scx + group, Scx Δ mice demonstrated blunted tendon growth. Transcriptional and proteomic analyses revealed significant reductions in cell proliferation, protein synthesis, and extracellular matrix genes and proteins. Our results indicate that scleraxis is required for mechanically-stimulated adult tendon growth by causing the commitment of CD146 + pericytes into the tenogenic lineage, and by promoting the initial expansion of newly committed tenocytes and the production of extracellular matrix proteins.

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Scleraxis is required for maturation of tissue domains for proper integration of the musculoskeletal system

Cited by 89 publications

References 42 publications

Loss of tenomodulin expression is a risk factor for age‐related intervertebral disc degeneration

Loss of tenomodulin expression is a risk factor for age‐related intervertebral disc degeneration

Potential biomarkers of the mature intervertebral disc identified at the single cell level

Scleraxis is required for the growth of adult tendons in response to mechanical loading

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