<i>Mkx</i>-Deficient Mice Exhibit Hedgehog Signaling–Dependent Ectopic Ossification in the Achilles Tendons

Liu, Han; Xu, Jingyue; Jiang, Rulang

doi:10.1002/jbmr.3630

Cited by 28 publications

(23 citation statements)

References 75 publications

(118 reference statements)

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“…A recent study showed that Gli1labeled adult mesenchymal stem/progenitor cells contributed to endochondral heterotopic ossification (7). Ablation of Hh signaling can inhibit the HO process in an Mkx-deficient mouse model and trauma-induced HO mouse model (35,36). Activating Hh signaling is…”

Section: Discussionmentioning

confidence: 99%

Tendon-derived cathepsin K–expressing progenitor cells activate Hedgehog signaling to drive heterotopic ossification

Feng

Xing

Han

et al. 2020

Journal of Clinical Investigation

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Heterotopic ossification (HO) is pathological bone formation characterized by ossification within muscle, tendons, or other soft tissues. However, the cells of origin and mechanisms involved in the pathogenesis of HO remain elusive. Here we show that deletion of Suppressor of fused (Sufu) in Cathepsin K-Cre-expressing (Ctsk-Cre-expressing) cells resulted in spontaneous and progressive ligament, tendon, and periarticular ossification. Lineage tracing studies and cell functional analysis demonstrated that Ctsk-Cre could label a subpopulation of tendon-derived progenitor cells (TDPCs) marked by tendon marker Scleraxis (Scx). Ctsk + Scx + TDPCs are enriched for tendon stem cell markers and show the highest self-renewal capacity and differentiation potential. Sufu deficiency caused enhanced chondrogenic and osteogenic differentiation of Ctsk-Cre-expressing tendonderived cells via upregulating Hedgehog (Hh) signaling. Furthermore, pharmacological intervention of hedgehog signaling using JQ1 suppressed the development of HO. Thus, our results display that Cathepsin K-Cre labels a subpopulation of TDPCs contributing to HO and their cell fate changes are driven by activation of Hh signaling.

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Section: Discussionmentioning

confidence: 99%

Tendon-derived cathepsin K–expressing progenitor cells activate Hedgehog signaling to drive heterotopic ossification

Feng

Xing

Han

et al. 2020

Journal of Clinical Investigation

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“…The MKX [ 42 , 43 ] as well as SCX [ 44 ] have been identified as essential transcription factors in tendon development. While Scx -deficiency induces defects in tendon formation [ 45 ], Mkx -deficiency leads to defects in tendon tissue maturation [ 43 ] and heterotopic ossification in rodents [ 46 , 47 ]. Interestingly, Mkx null tendon-derived cells have stronger potential to induce chondrogenic differentiation while overexpression of Mkx inhibits chondrogenic differentiation [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Control of glucose metabolism is important in tenogenic differentiation of progenitors derived from human injured tendons

et al. 2019

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Glucose metabolism is altered in injured and healing tendons. However, the mechanism by which the glucose metabolism is involved in the pathogenesis of tendon healing process remains unclear. Injured tendons do not completely heal, and often induce fibrous scar and chondroid lesion. Because previous studies have shown that tendon progenitors play roles in tendon repair, we asked whether connective tissue progenitors appearing in injured tendons alter glucose metabolism during tendon healing process. We isolated connective tissue progenitors from the human injured tendons, obtained at the time of primary surgical repair of rupture or laceration. We first characterized the change in glucose metabolism by metabolomics analysis using [1,2-13C]-glucose using the cells isolated from the lacerated flexor tendon. The flux of glucose to the glycolysis pathway was increased in the connective tissue progenitors when they proceeded toward tenogenic and chondrogenic differentiation. The influx of glucose to the tricarboxylic acid (TCA) cycle and biosynthesis of amino acids from the intermediates of the TCA cycle were strongly stimulated toward chondrogenic differentiation. When we treated the cultures with 2-deoxy-D-glucose (2DG), an inhibitor of glycolysis, 2DG inhibited chondrogenesis as characterized by accumulation of mucopolysaccharides and expression of AGGRECAN. Interestingly, 2DG strongly stimulated expression of tenogenic transcription factor genes, SCLERAXIS and MOHAWK under both chondrogenic and tenogenic differentiation conditions. The findings suggest that control of glucose metabolism is beneficial for tenogenic differentiation of connective tissue progenitors.

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“…The Scx-dependent target genes also include three genes encoding transcription factors, Mkx , Six2 , and Eya1 ( Table 1 ). Mkx function is required for tendon fibril growth and tendon homeostasis ( Ito et al, 2010 ; Liu et al, 2010 , 2019 ; Suzuki et al, 2016 ).…”

Section: Resultsmentioning

confidence: 99%

The Scleraxis Transcription Factor Directly Regulates Multiple Distinct Molecular and Cellular Processes During Early Tendon Cell Differentiation

Liu

Lan

et al. 2021

Front. Cell Dev. Biol.

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Proper development of tendons is crucial for the integration and function of the musculoskeletal system. Currently little is known about the molecular mechanisms controlling tendon development and tendon cell differentiation. The transcription factor Scleraxis (Scx) is expressed throughout tendon development and plays essential roles in both embryonic tendon development and adult tendon healing, but few direct target genes of Scx in tendon development have been reported and genome-wide identification of Scx direct target genes in vivo has been lacking. In this study, we have generated a ScxFlag knockin mouse strain, which produces fully functional endogenous Scx proteins containing a 2xFLAG epitope tag at the carboxy terminus. We mapped the genome-wide Scx binding sites in the developing limb tendon tissues, identifying 12,097 high quality Scx regulatory cis-elements in-around 7,520 genes. Comparative analysis with previously reported embryonic tendon cell RNA-seq data identified 490 candidate Scx direct target genes in early tendon development. Furthermore, we characterized a new Scx gene-knockout mouse line and performed whole transcriptome RNA sequencing analysis of E15.5 forelimb tendon cells from Scx–/– embryos and control littermates, identifying 68 genes whose expression in the developing tendon tissues significantly depended on Scx function. Combined analysis of the ChIP-seq and RNA-seq data yielded 32 direct target genes that required Scx for activation and an additional 17 target genes whose expression was suppressed by Scx during early tendon development. We further analyzed and validated Scx-dependent tendon-specific expression patterns of a subset of the target genes, including Fmod, Kera, Htra3, Ssc5d, Tnmd, and Zfp185, by in situ hybridization and real-time quantitative polymerase chain reaction assays. These results provide novel insights into the molecular mechanisms mediating Scx function in tendon development and homeostasis. The ChIP-seq and RNA-seq data provide a rich resource for aiding design of further studies of the mechanisms regulating tendon cell differentiation and tendon tissue regeneration. The ScxFlag mice provide a valuable new tool for unraveling the molecular mechanisms involving Scx in the protein interaction and gene-regulatory networks underlying many developmental and disease processes.

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Mkx-Deficient Mice Exhibit Hedgehog Signaling–Dependent Ectopic Ossification in the Achilles Tendons

Cited by 28 publications

References 75 publications

Tendon-derived cathepsin K–expressing progenitor cells activate Hedgehog signaling to drive heterotopic ossification

Tendon-derived cathepsin K–expressing progenitor cells activate Hedgehog signaling to drive heterotopic ossification

Control of glucose metabolism is important in tenogenic differentiation of progenitors derived from human injured tendons

The Scleraxis Transcription Factor Directly Regulates Multiple Distinct Molecular and Cellular Processes During Early Tendon Cell Differentiation

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