Formation of the sacrum requires down-regulation of sonic hedgehog signaling in the sacral intervertebral discs

Bonavita, Raffaella; Vincent, Kathleen; Pinelli, Robert; Dahia, Chitra Lekha

doi:10.1242/bio.035592

Cited by 14 publications

(31 citation statements)

References 25 publications

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“…These observations suggest that the unidentified pericellular structure described by Trout et al () around the nested CLCs is generated by the fusion of cell membranes of several NP cells as they form a syncytia. Next, we analysed whether the differentiated NP cells continued to express SHH, which is crucial for proliferation and maintenance of the reticular structure of NP cells in the neonatal mouse lumbar disc (Dahia, Mahoney, & Wylie, ) and sacral disc (Bonavita, Vincent, Pinelli, & Dahia, ). Shh expression is known to decline from postnatal day four to one year of age in mouse NP cells (Dahia, Mahoney, Durrani, & Wylie, ; Winkler et al, ).…”

Section: Introduction/results/discussionmentioning

confidence: 99%

“…In 18M old Shh LacZ mouse disc, 14.9% of CLC‐NP cells were β‐gal+ (Figure o and q). Results from previous studies show that SHH regulates expression of Brachyury ( Bra/T ) (Bonavita et al, ; Dahia et al, ), a key developmental molecule; hence, we analysed the expression of Bra , in CLC‐NP using its reporter allele where nuclear GFP is expressed under Bra promoter but inserted after the coding sequence of Bra gene ( T ‐nGFP , [Imuta, Kiyonari, Jang, Behringer, & Sasaki, ]). 28.8% of CLC‐NP cells were TnGFP+ in 16M old mouse lumbar discs (Figure p–q).…”

Section: Introduction/results/discussionmentioning

confidence: 99%

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Chondrocyte‐like nested cells in the aged intervertebral disc are late‐stage nucleus pulposus cells

et al. 2019

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Aging is a major risk factor of intervertebral disc degeneration and a leading cause of back pain. Pathological changes associated with disc degeneration include the absence of large, vacuolated and reticular‐shaped nucleus pulposus cells, and appearance of smaller cells nested in lacunae. These small nested cells are conventionally described as chondrocyte‐like cells; however, their origin in the intervertebral disc is unknown. Here, using a genetic mouse model and a fate mapping strategy, we have found that the chondrocyte‐like cells in degenerating intervertebral discs are, in fact, nucleus pulposus cells. With aging, the nucleus pulposus cells fuse their cell membranes to form the nested lacunae. Next, we characterized the expression of sonic hedgehog (SHH), crucial for the maintenance of nucleus pulposus cells, and found that as intervertebral discs age and degenerate, expression of SHH and its target Brachyury is gradually lost. The results indicate that the chondrocyte‐like phenotype represents a terminal stage of differentiation preceding loss of nucleus pulposus cells and disc collapse.

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Section: Introduction/results/discussionmentioning

confidence: 99%

Section: Introduction/results/discussionmentioning

confidence: 99%

Chondrocyte‐like nested cells in the aged intervertebral disc are late‐stage nucleus pulposus cells

et al. 2019

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“…The presence of progenitor cells was also reported in human disc samples (Risbud et al, ). In a study of skeletally mature 12‐week‐old mice, it was found that only a subset of nucleus pulposus cells expressed the notochord marker CK19 in the sacral disc (Bonavita et al, ), supplying further evidence of increasing molecular heterogeneity in nucleus pulposus cells with aging. It is not yet known if this age‐related increase in molecular heterogeneity among sacral disc nucleus pulposus cells is a feature of other regions of the spine.…”

Section: Potential Therapies For Disc Regeneration and Treatment Of Bmentioning

confidence: 99%

“…In this same time frame, the responses to key developmental signaling pathways including SHH, WNT, BMP, TGFb, and PTHrP in all components of the disc are also reduced (Dahia et al, ). Expression of BRA, a downstream target of SHH, in the mouse lumbar and sacral disc is also reduced with age (Bonavita et al, ; Dahia et al, ; Winkler et al, ). Interestingly, expression of BRA is not uniform among nucleus pulposus cells, which suggests cellular heterogeneity among the nucleus pulposus cells during postnatal growth and aging (Dahia et al, ).…”

Section: Molecular and Pathological Changes In The Disc With Aging Anmentioning

confidence: 99%

“…With age, nucleus pulposus cells also develop cellular heterogeneity, and maybe only a subset of them are capable of maintaining the disc microenvironment and health (Bonavita et al, ; Dahia et al, ; Risbud et al, ; Sakai et al, ). Under this hypothesis, stimulating the progenitor nucleus pulposus cells without introducing exogenously sourced cells may yield better outcomes (Figure ), as was shown in mouse sacral discs (Bonavita et al, ). However, critical questions going forward are: Why does the expression of these developmental signals decline with age?…”

Section: Conclusion and Perspectivementioning

confidence: 99%

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Defects in intervertebral disc and spine during development, degeneration, and pain: New research directions for disc regeneration and therapy

Mohanty

Dahia

2019

WIREs Developmental Biology

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Intervertebral discs are cartilaginous joints present between vertebrae. The centers of the intervertebral discs consist of a gelatinous nucleus pulposus derived from the embryonic notochord. With age or injury, intervertebral discs may degenerate, causing neurological symptoms including back pain, which affects millions of people worldwide. Back pain is a multifactorial disorder, and disc degeneration is one of the primary contributing factors. Recent studies in mice have identified the key molecules involved in the formation of intervertebral discs. Several of these key molecules including sonic hedgehog and Brachyury are not only expressed by notochord during development, but are also expressed by neonatal mouse nucleus pulposus cells, and are crucial for postnatal disc maintenance. These findings suggest that intrinsic signals in each disc may maintain the nucleus pulposus microenvironment. However, since expression of these developmental signals declines with age and degeneration, disc degeneration may be related to the loss of these intrinsic signals. In addition, findings from mouse and other mammalian models have identified similarities between the patterning capabilities of the embryonic notochord and young nucleus pulposus cells, suggesting that mouse is a suitable model system to understand disc development and aging. Future research aimed at understanding the upstream regulators of these developmental signals and the modes by which they regulate disc growth and maintenance will likely provide mechanistic insights into disc growth and aging. Further, such findings will likely provide insights relevant to the development of effective therapies for treatment of back pain and reversing the disc degenerative process.

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Silencing MEKK3 attenuates cardiomyocyte injury caused by hypoxia/reoxygenation via the sonic hedgehog pathway

Wang

Yan

Wang

2019

Journal Cellular Physiology

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MEKK3 is a member of MAP3K, which plays a pivotal role in cardiac diseases. In this study, we aimed to investigate the effects and potential mechanisms of MEKK3 on hypoxia/reoxygenation (H/R) injury of cardiomyocytes. After exposing H9C2 cells to H/R insult, real‐time polymerase chain reaction and western blot analysis showed that MEKK3 was highly expressed. Cell viability, cell apoptosis, caspase 3/7 activity, and cleaved‐caspase 3 expression were tested using a CCK‐8 assay, Cell Death Detection PLUS ELISA, Caspase‐Glo 3/7 Assay Kit and western blot analysis, respectively. Mitochondrial membrane potential, cytochrome C expression, adenosine triphosphate (ATP), and reactive oxygen species also were measured using JC‐1 staining, western blot analysis, an ATP Assay Kit, and DCFH 2‐DA staining, respectively. The messenger RNA (mRNA) levels and secretions of TNF‐α, IL‐6, and IL‐1β were evaluated. The results revealed that MEKK3 silencing promoted cell survival and attenuated lactate dehydrogenase leakage, cell apoptosis, caspase 3/7 activity, and the protein level of cleaved‐caspase 3. Moreover, knockdown of MEKK3 blocked mitochondrial impairment by inhibiting the loss of mitochondrial membrane potential and cytochrome C expression as well as promoting ATP synthesis. MEKK3 deficiency led to a decrease in reactive oxygen species and malondialdehyde (MDA) generation and an increase in superoxide dismutase (SOD) activity. Deletion of MEKK3 led to reduced inflammatory cytokines in mRNA level and secretion. MEKK3 suppression activated the sonic hedgehog (Shh) signaling pathway in H9C2 cells. After blocking the Shh signaling pathway with a specific inhibitor, cyclopamine, the cardioprotective functions of MEKK3 downregulation were partly abolished. In conclusion, downregulation of MEKK3 prevented apoptosis and inflammation in H9C2 cells via the Shh signaling pathway.

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Formation of the sacrum requires down-regulation of sonic hedgehog signaling in the sacral intervertebral discs

Cited by 14 publications

References 25 publications

Chondrocyte‐like nested cells in the aged intervertebral disc are late‐stage nucleus pulposus cells

Chondrocyte‐like nested cells in the aged intervertebral disc are late‐stage nucleus pulposus cells

Defects in intervertebral disc and spine during development, degeneration, and pain: New research directions for disc regeneration and therapy

Silencing MEKK3 attenuates cardiomyocyte injury caused by hypoxia/reoxygenation via the sonic hedgehog pathway

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