A radical switch in clonality reveals a stem cell niche in the epiphyseal growth plate

Newton, Phillip T; Li, Lei; Zhou, Baoyi; Schweingruber, Christoph; Hovořáková, Mária; Xie, Meng; Sun, Xiaoyan; Sandhow, Lakshmi; Av, Artemov; Ivashkin, Evgeny; Suter, Simon; Dyachuk, Vyacheslav; Shahawy, Maha El; Gritli-Linde, Amel; Bouderlique, Thibault; Petersen, Julian; Mollbrink, Annelie; Lundeberg, Joakim; Enikolopov, Grigori; Qian, Hong; Fried, Kaj; Kasper, Maria; Hedlund, Eva; Adameyko, Igor; Sävendahl, Lars; Chagin, Andrei S.

doi:10.1038/s41586-019-0989-6

Cited by 179 publications

(286 citation statements)

References 39 publications

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“…Our data indicate that SDC3's regulatory role extends into adulthood as SDC3 deletion leads at 3 months of age to a thin growth plate with disorganised columns of chondrocytes within the proliferating zone, which is associated with mild, but significant long bone growth stunting compared to the reverse seen in utero. This growth plate abnormality may be due to defective chondrogenesis at stem cell level in the growth plate resting zone 46,47 , and/or at the proliferation and differentiation stages of chondrocytes 19,20 , in which extracellular matrix, with which transmembrane HSPGs interact, is thought to play a role. Further investigations are in progress to assess the exact role of SDC3 in the regulation of chondrocytes within the growth plate and in longitudinal bone growth.…”

Section: Discussionmentioning

confidence: 99%

Syndecan-3 enhances anabolic bone formation through WNT signalling

Brito

Butcher

Pisconti

et al. 2019

Preprint

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Osteoporosis is the most common age-related metabolic bone disorder, which is characterised by low bone mass and deterioration in bone architecture, with a propensity to fragility fractures. The best treatment for osteoporosis relies on stimulation of osteoblasts to form new bone and restore bone structure, however anabolic therapeutics are few and their use is timerestricted. Here we report that Syndecan-3 (SDC3) increases new bone formation through enhancement of WNT signalling. Young adult Sdc3 -/mice have a low bone volume phenotype associated with reduced bone formation, increased bone marrow adipose tissue (BMAT), increased bone fragility and a blunted anabolic bone formation response to mechanical loading. The premature osteoporosis-like phenotype of Sdc3 -/mice is primarily explained by delayed osteoblast maturation and impaired osteoblast function, with contributing increased osteoclast-mediated bone resorption. Mechanistically, SDC3 enhances canonical WNT signalling in osteoblasts through stabilisation of Frizzled 1, making SDC3 an attractive target for novel anabolic drug development. KEY WORDS Syndecan-3, bone, osteoblast, osteoclast, WNT, Frizzled

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Section: Discussionmentioning

confidence: 99%

Syndecan-3 enhances anabolic bone formation through WNT signalling

Brito

Butcher

Pisconti

et al. 2019

Preprint

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“…The growth plate can be divided into a resting zone that contains round cartilage cells (chondrocytes); a zone that is formed by columns of flat, proliferating chondrocytes; and a zone comprising large (hypertrophic), non-proliferating chondrocytes. Newton et al 1 show that the resting zone contains stem cells (red) that form monoclonal (originating from a single cell) columns of flat and hypertrophic chondrocytes, some of which become bone-forming cells (osteoblasts) or stem cells of the bone-marrow stroma (which are not from the blood-cell lineage). One resting-zone stem cell and the descendants of that single cell have a dashed outline.…”

Section: The Fountain Of Bone Growthmentioning

confidence: 99%

“…But certain aspects of their mathematical foundations are also strikingly similar. On page 209, Havlíček et al 1 exploit this link to show how today's quantum computers can, in principle, be used to learn from data -by mapping data into the space in which only quantum states exist.…”

Section: This Article Was Published Online On 27 February 2019 M a Rmentioning

confidence: 99%

“…Consequently, growth-plate chondrocytes need to be replenished continuously and the stem cells that fuel this process have long been sought. On page 234, Newton et al 1 and, previously, Mizuhashi et al 2 have identified a type of skeletal stem cell in the resting zone of mouse bones that gives rise to all types of growth-plate chondrocyte, as well as some of the long-lived stem cells of the bone-marrow stroma (non-blood-lineage cells).…”

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confidence: 99%

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A newly discovered stem cell that keeps bones growing

Wuelling

Vortkamp

2019

Nature

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“…The model can also be used to assess cell proliferation, which is particularly useful for studying slowly dividing cells. For example, clonal formation in the articular cartilage 12 was assessed, and the short-term effects of a hedgehog antagonist on growth plate chondrocytes in five-week old mice was studied 13 .…”

Section: Introductionmentioning

confidence: 99%

Clonal Genetic Tracing using the Confetti Mouse to Study Mineralized Tissues

Zhou

Kaucká

Chagin

et al. 2019

JoVE

Self Cite

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Labeling an individual cell in the body to monitor which cell types it can give rise to and track its migration through the organism or determine its longevity can be a powerful way to reveal mechanisms of tissue development and maintenance. One of the most important tools currently available to monitor cells in vivo is the Confetti mouse model. The Confetti model can be used to genetically label individual cells in living mice with various fluorescent proteins in a cell type-specific manner and monitor their fate, as well as the fate of their progeny over time, in a process called clonal genetic tracing or clonal lineage tracing. This model was generated almost a decade ago and has contributed to an improved understanding of many biological processes, particularly related to stem cell biology, development, and renewal of adult tissues. However, preserving the fluorescent signal until image collection and simultaneous capturing of various fluorescent signals is technically challenging, particularly for mineralized tissue. This publication describes a step-by-step protocol for using the Confetti model to analyze growth plate cartilage that can be applied to any mineralized or nonmineralized tissue.

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A radical switch in clonality reveals a stem cell niche in the epiphyseal growth plate

Cited by 179 publications

References 39 publications

Syndecan-3 enhances anabolic bone formation through WNT signalling

Syndecan-3 enhances anabolic bone formation through WNT signalling

A newly discovered stem cell that keeps bones growing

Clonal Genetic Tracing using the Confetti Mouse to Study Mineralized Tissues

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