Primary cilia as the nexus of biophysical and hedgehog signaling at the tendon enthesis

Fang, Fei; Schwartz, Andrea G.; Moore, Emily R.; Sup, McKenzie E.; Thomopoulos, Stavros

doi:10.1126/sciadv.abc1799

Cited by 31 publications

(33 citation statements)

References 51 publications

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“…Mouse organs or soft tissues from 4-week-old ARL13B-mCherry; Centrin2-GFP cilium dual reporter-expressing transgenic mice ( n = 6) were fixed with 10% neutral buffered formalin for 1–2 h at 4 °C [ 7 , 8 ]. Mouse femurs and intervertebral discs from between the third and fifth vertebrae in the lumbar spine and between the fifth and sixth coccygeal vertebrae ( n = 6) were excised, fixed with 10% neutral buffered formalin, and decalcified in 10% ethylenediaminetetraacetic acid (EDTA) for 2–3 weeks at 4 °C.…”

Section: Methodsmentioning

confidence: 99%

Identification of Cilia in Different Mouse Tissues

Yang

Deepak

et al. 2021

Cells

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Cilia are microtubule-based hair-like organelles that extend from the cell surface. However, the existence and distribution of cilia in each organ and tissue at the postnatal stage in vivo remain largely unknown. In this study, we defined cilia distribution and arrangement and measured the ciliary lengths and the percentage of ciliated cells in different organs and tissues in vivo by using cilium dual reporter-expressing transgenic mice. Cilia were identified by the presence of ARL13B with an mCherry+ signal, and the cilium basal body was identified by the presence of Centrin2 with a GFP+ signal. Here, we provide in vivo evidence that chondrocytes and cells throughout bones have cilia. Most importantly, we reveal that: 1. primary cilia are present in hepatocytes; 2. no cilia but many centrioles are distributed on the apical cell surface in the gallbladder, intestine, and thyroid epithelia; 3. cilia on the cerebral cortex are well oriented, pointing to the center of the brain; 4. ARL13B+ inclusion is evident in the thyroid and islets of Langerhans; and 5. approximately 2% of cilia show irregular movement in nucleus pulposus extracellular fluid. This study reveals the existence and distribution of cilia and centrioles in different tissues and organs, and provides new insights for further comprehensive study of ciliary function in these organs and tissues.

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Section: Methodsmentioning

confidence: 99%

Identification of Cilia in Different Mouse Tissues

Yang

Deepak

et al. 2021

Cells

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“…In this study, we show that SHH is synthesized by OA cartilage mesenchymal stromal cells and plays an important role in regulating MSC growth, replicative senescence, and chondrocyte catabolism as well as apoptosis during OA pathogenesis. Previously, SHH has been shown to be a key molecule to regulate embryonic morphogenesis of skeletal tissues including meniscus ( Wei et al, 2021 ), tendon enthesis ( Fang et al, 2020 ), and limb bud ( Alman, 2015 ). Synthesized by mesenchymal progenitor cells, SHH affects different types of cells located nearby to regulate tissue morphogenesis, maintain organ homeostasis, and drive tissue aging ( Ho et al, 2009 ; Lin et al, 2014 ; Ali et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

“…Blocking hedgehog (HH) signaling attenuates cartilage degeneration and OA pathogenesis ( Lin et al, 2009 ), although the precise molecular mechanism remains unclear. Canonical signaling of HH is mediated by a multi-component receptor complex that includes Patched homolog 1 (PTCH1), Smoothened (SMO), and the Gli family of transcription factors ( Alman, 2015 ; Fang et al, 2020 ). While PTCH1 inhibits SMO and downstream transcription factors, the binding of HH to PTCH1 receptor releases the basal inhibition of SMO by PTCH1, thereby activating recipient cell activity ( Woods et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Sonic Hedgehog Induces Mesenchymal Stromal Cell Senescence-Associated Secretory Phenotype and Chondrocyte Apoptosis in Human Osteoarthritic Cartilage

Feng

Liu

Ding

et al. 2021

Front. Cell Dev. Biol.

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Hedgehog (HH) signaling plays a critical role in osteoarthritis (OA) pathogenesis, but the molecular mechanism remains to be elucidated. We show here that Sonic Hedgehog (SHH) gene expression is initiated in human normal cartilage stromal cells (NCSC) and increased in OA cartilage mesenchymal stromal cells (OA-MSCs) during aging. Manifesting a reciprocal cellular distribution pattern, the SHH receptors PTCH1 and SMO and transcription factors GLI2 and GLI3 are expressed by chondrocytes (OAC) in OA cartilage. SHH autocrine treatment of osteoarthritis MSC stimulates proliferation, chondrogenesis, hypertrophy, and replicative senescence with elevated SASP gene expression including IL1B, IL6, CXCL1, and CXCL8. SHH paracrine treatment of OAC suppresses COL2A1, stimulates MMP13, and induces chondrocyte apoptosis. The OA-MSC conditioned medium recapitulates the stimulatory effects of SHH on OAC catabolism and apoptosis. SHH knock-down in OA-MSC not only inhibits catabolic and senescence marker expression in OA-MSC, but also abolishes the effect of the OA-MSC conditioned medium on OAC catabolism and apoptosis. We propose that SHH is a key mediator between OA-MSC and OA chondrocytes interaction in human OA cartilage via two mechanisms: (1) SHH mediates MSC growth and aging by activating not only its proliferation and chondrogenesis, but also low-grade inflammation and replicative senescence, and (2) SHH mediates OA-MSC-induced OAC catabolism and apoptosis by creating a pro-inflammatory microenvironment favoring tissue degeneration during OA pathogenesis.

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“…Cilia have been proposed to play a critical role in mechanotransduction in chondrocytes and/or the GP before, on the basis of both correlations between loading and cilia prevalence in situ (45) and in vitro evidence from chondrocyte cell lines (6,45,62). Cilia have recently been shown to play a critical role integrating mechanical loading and force in tendon (63).…”

Section: Discussionmentioning

confidence: 99%

Ciliary IFT88 safeguards coordinated epiphyseal vascularisation, resorption and ossification from disruptive physiological mechanical forces

Coveney

Samvelyan

Miotla‐Zarebska

et al. 2021

Preprint

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In the musculoskeletal system, appropriate cell and tissue responses to mechanical force delineate morphogenesis and ensure lifelong health. Despite this, how mechanical cues are integrated into biological programmes remains unclear. Primary cilia are microtubule-based organelles that tune a range of cell activities, including signalling cascades activated or modulated, by extracellular biophysical cues. Here, we demonstrate that the inducible, cartilage-specific deletion of Intraflagellar transport protein 88 (IFT88), which reduces ciliation in the adolescent mouse growth plate (GP), uncouples chondrocyte differentiation from cartilage resorption and mineralisation in a mechano-dependent manner. Targeting IFT88, inhibits hypertrophic chondrocyte VEGF expression, vascular recruitment, osteoclastic activity and the replacement of cartilage with bone. These effects are largely restricted to peripheral tibial regions beneath the load-bearing compartments of the knee. Increases in physiological loading, in control mice, also impairs ossification in the peripheral GP, mimicking the effects of IFT88 deletion. Strikingly, limb immobilisation rescues disrupted VEGF and restores epiphyseal dynamics in Ift88cKO mice. These data indicate, that during this pivotal phase in adolescent skeletal maturation that defines the cessation of growth, ciliary IFT88 protects the coordinated ossification of the growth plate from an otherwise disruptive heterogeneity of physiological mechanical forces.

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Primary cilia as the nexus of biophysical and hedgehog signaling at the tendon enthesis

Cited by 31 publications

References 51 publications

Identification of Cilia in Different Mouse Tissues

Identification of Cilia in Different Mouse Tissues

Sonic Hedgehog Induces Mesenchymal Stromal Cell Senescence-Associated Secretory Phenotype and Chondrocyte Apoptosis in Human Osteoarthritic Cartilage

Ciliary IFT88 safeguards coordinated epiphyseal vascularisation, resorption and ossification from disruptive physiological mechanical forces

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