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

Feng, Heng; Xing, Wenhui; Han, Yujiao; Sun, Jun; Kong, Mingxiang; Gao, Bo; Yang, Yang; Yin, Zi; Chen, Xiao; Zhao, Yun; Bi, Qing; Zou, Weiguo

doi:10.1172/jci132518

Cited by 69 publications

(68 citation statements)

References 49 publications

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“…9E) [41–43]. Interestingly, HO-associated with increased HH signalling was suppressed by the BRD4 inhibitor JQ1 [44], which clearly demonstrated a role for a cAMP-PKA-BRD4-GLI1 axis in skeletal tissue homeostasis. A non-canonical role of SMO as a G protein-coupled receptor (14, 15) provides a mechanism to control PKA activity.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin-protein ligaseUbr5cooperates with Hedgehog signalling to promote skeletal tissue homeostasis

Mellis

Staines

Peluso

et al. 2020

Preprint

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Mammalian Hedgehog (HH) signalling pathway plays an essential role in tissue homeostasis and its deregulation is linked to rheumatological disorders. UBR5 is the mammalian homologue of the E3 ubiquitin-protein ligase Hyd, a negative regulator of the Hh-pathway in Drosophila. To investigate a possible role of UBR5 in regulation of the musculoskeletal system through modulation of mammalian HH signaling, we created a mouse model for specific loss of Ubr5 function in limb bud mesenchyme. Our findings revealed a role for UBR5 in maintaining cartilage homeostasis and suppressing metaplasia. Ubr5 loss of function resulted in progressive and dramatic articular cartilage degradation, enlarged, abnormally shaped sesamoid bones and extensive heterotopic tissue metaplasia linked to calcification of tendons and ossification of synovium. Genetic suppression of smoothened (Smo), a key mediator of HH signalling, dramatically enhanced the Ubr5 mutant phenotype. Analysis of HH signalling in both mouse and cell model systems revealed that loss of Ubr5 stimulated canonical HH-signalling while also increasing PKA activity. In addition, human osteoarthritic samples revealed similar correlations between UBR5 expression, canonical HH signalling and PKA activity markers. Our studies identified a crucial function for the Ubr5 gene in the maintenance of skeletal tissue homeostasis and an unexpected mode of regulation of the HH signalling pathway.Author SummaryUbiquitin ligases modify proteins post-translationally which is essential for a variety of cellular processes. UBR5 is an E3 ubiquitin ligase and in Drosophila is a regulator of Hedgehog signaling. In mammals, the Hedgehog (HH) signalling pathway, among many other roles, plays an essential role in tissue maintenance, a process called homeostasis. A murine genetic system was developed to specifically eliminate UBR5 function from embryonic limb tissue that subsequently forms bone and connective tissue (ligaments and tendons). This approach revealed that UBR5 operates as a potent suppressor of excessive growth of normal cartilage and bone and prevents formation of bone in ectopic sites in connective tissue near the knees and ankle joints. In contrast to abnormal growth, UBR5 inhibits degradation of the articular cartilage that cushions the knee joint leading to extensive exposure of underlying bone. Furthermore, Ubr5 interacts with smoothened, a component of the HH pathway, identifying UBR5 as a regulator of mammalian HH signaling in the postnatal musculoskeletal system. In summary, this work shows that UBR5 interacts with the HH pathway to regulate skeletal homeostasis in and around joints of the legs and identifies targets that may be harnessed for biomedical engineering and clinical applications.

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Section: Discussionmentioning

confidence: 99%

Ubiquitin-protein ligaseUbr5cooperates with Hedgehog signalling to promote skeletal tissue homeostasis

Mellis

Staines

Peluso

et al. 2020

Preprint

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“…Rigorous studies on various subpopulations of TSPCs deepen our understanding of the elusive mechanism of tendon pathological healing. A Cathepsin K (Ctsk) expressing TSPCs subpopulation present at mid-substance had been identified, which contribute to heterotopic ossification ( Feng et al, 2020 ). Ctsk is a proven marker of osteoclasts, periosteal stem cells and perichondrial progenitors ( Nakamura et al, 2007 ; Yang et al, 2013 ; Debnath et al, 2018 ).…”

Section: Tspcs In Tendon Biologymentioning

confidence: 99%

“…Ctsk is a proven marker of osteoclasts, periosteal stem cells and perichondrial progenitors ( Nakamura et al, 2007 ; Yang et al, 2013 ; Debnath et al, 2018 ). Ctsk + Scx + TSPCs possess great self-renewal capacity and differentiation potentials with enriched progenitor cell markers ( Feng et al, 2020 ). The depletion of the Suppressor of fused followed by activation of Hh signaling would trigger subsequent chondrogenesis and osteogenesis of Ctsk + Scx + TSPCs ( Feng et al, 2020 ).…”

Section: Tspcs In Tendon Biologymentioning

confidence: 99%

“…Ctsk + Scx + TSPCs possess great self-renewal capacity and differentiation potentials with enriched progenitor cell markers ( Feng et al, 2020 ). The depletion of the Suppressor of fused followed by activation of Hh signaling would trigger subsequent chondrogenesis and osteogenesis of Ctsk + Scx + TSPCs ( Feng et al, 2020 ).…”

Section: Tspcs In Tendon Biologymentioning

confidence: 99%

“…TGFβ/SMAD2/3 signaling is required for Scx expression in undifferentiated tendon progenitors and essential for tendon development, which might regulate later recruitment of tendon cells ( Pryce et al, 2009 ; Havis et al, 2016 ). Other than serving as a potent inducer of Scleraxis expression and a strong recruiter of tendon progenitors, TGFβ also maintained Scx expression of TSPCs in vitro ( Asai et al, 2014 ; Feng et al, 2020 ). Additionally, TGFβ balance the expression of Sox9 and Scx expression within a pool of progenitor cells and thus modulate their chondrogenic and tenogenic differentiation ( Blitz et al, 2013 ; Sugimoto et al, 2013 ).…”

Section: Tspcs In Tendon Biologymentioning

confidence: 99%

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Tendon Stem/Progenitor Cell Subpopulations and Their Implications in Tendon Biology

Huang

Yin

et al. 2021

Front. Cell Dev. Biol.

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Tendon harbors a cell population that possesses stem cell characteristics such as clonogenicity, multipotency and self-renewal capacity, commonly referred to as tendon stem/progenitor cells (TSPCs). Various techniques have been employed to study how TSPCs are implicated in tendon development, homeostasis and healing. Recent advances in single-cell analysis have enabled much progress in identifying and characterizing distinct subpopulations of TSPCs, which provides a more comprehensive view of TSPCs function in tendon biology. Understanding the mechanisms of physiological and pathological processes regulated by TSPCs, especially a particular subpopulation, would greatly benefit treatment of diseased tendons. Here, we summarize the current scientific literature on the various subpopulations of TSPCs, and discuss how TSPCs can contribute to tissue homeostasis and pathogenesis, as well as examine the key modulatory signaling pathways that determine stem/progenitor cell state. A better understanding of the roles that TSPCs play in tendon biology may facilitate the development of novel treatment strategies for tendon diseases.

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Spatiotemporal Characterization of Human Early Intervertebral Disc Formation at Single‐Cell Resolution

et al. 2023

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The intervertebral disc (IVD) acts as a fibrocartilaginous joint to anchor adjacent vertebrae. Although several studies have demonstrated the cellular heterogeneity of adult mature IVDs, a single‐cell transcriptomic atlas mapping early IVD formation is still lacking. Here, the authors generate a spatiotemporal and single cell‐based transcriptomic atlas of human IVD formation at the embryonic stage and a comparative mouse transcript landscape. They identify two novel human notochord (NC)/nucleus pulposus (NP) clusters, SRY‐box transcription factor 10 (SOX10)+ and cathepsin K (CTSK)+, that are distributed in the early and late stages of IVD formation and they are validated by lineage tracing experiments in mice. Matrisome NC/NP clusters, T‐box transcription factor T (TBXT)+ and CTSK+, are responsible for the extracellular matrix homeostasis. The IVD atlas suggests that a subcluster of the vertebral chondrocyte subcluster might give rise to an inner annulus fibrosus of chondrogenic origin, while the fibroblastic outer annulus fibrosus preferentially expresseds transgelin and fibromodulin . Through analyzing intercellular crosstalk, the authors further find that notochordal secreted phosphoprotein 1 (SPP1) is a novel cue in the IVD microenvironment, and it is associated with IVD development and degeneration. In conclusion, the single‐cell transcriptomic atlas will be leveraged to develop preventative and regenerative strategies for IVD degeneration.

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

Cited by 69 publications

References 49 publications

Ubiquitin-protein ligaseUbr5cooperates with Hedgehog signalling to promote skeletal tissue homeostasis

Ubiquitin-protein ligaseUbr5cooperates with Hedgehog signalling to promote skeletal tissue homeostasis

Tendon Stem/Progenitor Cell Subpopulations and Their Implications in Tendon Biology

Spatiotemporal Characterization of Human Early Intervertebral Disc Formation at Single‐Cell Resolution

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