Chondrocytes in the resting zone of the growth plate are maintained in a Wnt-inhibitory environment

Hallett, Shawn A; Ono, Wanida; Sakagami, Naoko; Mizuhashi, Koji; Tokavanich, Nicha; Zhou, Annabelle; Hanabusa, Takao; Kronenberg, Henry M.; Ono, Noriaki

doi:10.7554/elife.64513

Cited by 36 publications

(31 citation statements)

References 54 publications

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“…First, effects at the Rspo3 mRNA expression level have not been confirmed at the protein level. Second, RUNX2 is reported to be expressed in chondrocytes, and since RSPO3 also is expressed in a subset of chondrocytes in the growth plate ( 39 ), we cannot exclude the possibility that inactivation of RSPO3 expression in chondrocytes also might have contributed to the observed effects. Further mechanistic studies are required to identify differences in the pathways for E2 and RSPO3 to regulate vertebral trabecular bone mass.…”

Section: Discussionmentioning

confidence: 99%

Estradiol and RSPO3 regulate vertebral trabecular bone mass independent of each other

Nilsson

Gustafsson

et al. 2022

American Journal of Physiology-Endocrinology and Metabolism

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Osteoporosis is an age-dependent serious skeletal disease that leads to great suffering for the patient and high social costs, especially as the global population reaches higher age. Decreasing estrogen levels after menopause result in a substantial bone loss and increased fracture risk, while estrogen treatment improves bone mass in women. RSPO3, a secreted protein that modulates WNT signaling, increases trabecular bone mass and strength in the vertebrae of mice, and is associated with trabecular density and risk of distal forearm fractures in humans. The aim of the present study was to determine if RSPO3 is involved in the bone-sparing effect of estrogens. We first observed that estradiol (E2) treatment increases RSPO3 expression in bone of ovariectomized (OVX) mice, supporting a possible role of RSPO3 in the bone-sparing effect of estrogens. As RSPO3 is mainly expressed by osteoblasts in the bone, we used a mouse model devoid of osteoblast-derived RSPO3 (Runx2‑creRspo3flox/flox mice) to determine if RSPO3 is required for the bone-sparing effect of E2 in OVX mice. We confirmed that osteoblast-specific RSPO3 inactivation results in a substantial reduction in trabecular bone mass and strength in the vertebrae. However, E2 increased vertebral trabecular bone mass and strength similarly in mice devoid of osteoblast-derived RSPO3 and control mice. Unexpectedly, osteoblast-derived RSPO3 was needed for the full estrogenic response on cortical bone thickness. In conclusion, although osteoblast-derived RSPO3 is a crucial regulator of vertebral trabecular bone, it is required for a full estrogenic effect on cortical, but not trabecular, bone in OVX mice. Thus, estradiol and RSPO3 regulate vertebral trabecular bone mass independent of each other.

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Section: Discussionmentioning

confidence: 99%

Estradiol and RSPO3 regulate vertebral trabecular bone mass independent of each other

Nilsson

Gustafsson

et al. 2022

American Journal of Physiology-Endocrinology and Metabolism

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“…Although the similarity of these two processes requires further investigation, knowledge from cells within the epiphyseal growth plate should still be informative for future study of in vitro hypertrophy of chondroinduced MSCs. The comparison between resting and hypertrophic chondrocytes in the growth plate confirmed that the cells in the resting zone are maintained in a Wnt-inhibitory environment ( Hallett et al, 2021 ).…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 68%

Role of Canonical Wnt/β-Catenin Pathway in Regulating Chondrocytic Hypertrophy in Mesenchymal Stem Cell-Based Cartilage Tissue Engineering

Wang

Guan

Xiang

et al. 2022

Front. Cell Dev. Biol.

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In the past 3 decades, the cartilage repair potential of mesenchymal stromal cells, or mesenchymal stem cells (MSCs), has been widely examined in animal studies. Unfortunately, the phenotype and physical properties of MSC-derived cartilage tissue are not comparable to native hyaline cartilage. In particular, chondrocytic hypertrophy, a phenotype that is not observed in healthy hyaline cartilage, is concomitant with MSC chondrogenesis. Given that hypertrophic chondrocytes potentially undergo apoptosis or convert into osteoblasts, this undesired phenotype needs to be prevented or minimized before MSCs can be used to repair cartilage injuries in the clinic. In this review, we first provide an overview of chondrocytic hypertrophy and briefly summarize current methods for suppressing hypertrophy in MSC-derived cartilage. We then highlight recent progress on modulating the canonical Wnt/β-catenin pathway for inhibiting hypertrophy. Specially, we discuss the potential crosstalk between Wnt/β-catenin with other pathways in regulating hypertrophy. Lastly, we explore future perspectives to further understand the role of Wnt/β-catenin in chondrocytic hypertrophy.

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“…S10e). Representative genes upregulated in resting chondrocytes included previously reported markers for resting chondrocytes, such as Clu , 20 Gas1 , Wif1, 21 Efemp1 , and Sorl1 22 (Fig. S10e).…”

Section: Resultsmentioning

confidence: 94%

Nutrient-regulated dynamics of chondroprogenitors in the postnatal murine growth plate

Oichi

Kodama

Wilson

et al. 2023

Preprint

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Longitudinal bone growth relies on endochondral ossification in the cartilaginous growth plate where chondrocytes accumulate and synthesize the matrix scaffold that is replaced by bone. The　chondroprogenitors in the resting zone maintain the continuous turnover of chondrocytes in the growth plate. Malnutrition is a leading cause of growth retardation in children; however, after recovery from nutrient deprivation, bone growth is accelerated beyond the normal rate, a phenomenon termed catch-up growth. Though nutritional status is a known regulator of long bone growth, it is largely unknown if and how chondroprogenitor cells respond to deviations in nutrient availability. Here, using fate-mapping analysis in Axin2CreERT2 mice, we showed that dietary restriction increased the number of Axin2+ chondroprogenitors in the resting zone and simultaneously inhibited their differentiation. Once nutrient deficiency was resolved, the accumulated chondroprogenitor cells immediately restarted differentiation and formed chondrocyte columns, contributing to accelerated growth. Furthermore, we showed that nutrient deprivation reduced the level of phosphorylated Akt in the resting zone, and that exogenous IGF-1 canceled this reduction and stimulated differentiation of the pooled chondroprogenitors, decreasing their numbers. Our study ofAxin2CreERT2revealed that nutrient availability regulates the balance between accumulation and differentiation of chondroprogenitors in the growth plate, and further demonstrated that IGF-1 partially mediates this regulation by promoting the committed differentiation of the chondroprogenitor cells.

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Chondrocytes in the resting zone of the growth plate are maintained in a Wnt-inhibitory environment

Cited by 36 publications

References 54 publications

Estradiol and RSPO3 regulate vertebral trabecular bone mass independent of each other

Estradiol and RSPO3 regulate vertebral trabecular bone mass independent of each other

Role of Canonical Wnt/β-Catenin Pathway in Regulating Chondrocytic Hypertrophy in Mesenchymal Stem Cell-Based Cartilage Tissue Engineering

Nutrient-regulated dynamics of chondroprogenitors in the postnatal murine growth plate

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