Biology subjects

Ono, W.

Publications and source records attributed to Ono, W..

4 recordsLinked to original sources

bioRxiv2024

Control of alveolar bone development, homeostasis, and socket healing by salt inducible kinases

Alveolar bone supports and anchors teeth. The parathyroid hormone-related protein (PTHrP) pathway plays a key role in alveolar bone biology. Salt inducible kinases (SIKs) are important downstream regulators of PTH/PTHrP signaling in the appendicular skeleton where SIK inhibition increases bone formation and trabecular bone mass. However, the function of these kinases in alveolar bone remains unknown. Here, we report a critical role for SIK2/SIK3 in alveolar bone development, homeostasis, and socket healing after tooth extraction. Inducible SIK2/SIK3 deletion led to dramatic alveolar bone defects without changes in tooth eruption. Ablating these kinases impairs alveolar bone formation due to disrupted osteoblast maturation, a finding associated with ectopic periostin expression by fibrous cells in regions of absent alveolar bone at steady state and following molar extraction. Distinct phenotypic consequences of SIK2/SIK3 deletion in appendicular versus craniofacial bones prompted us to identify a specific transcriptomic signature in alveolar versus long bone osteoblasts. Thus, SIK2/SIK3 deletion illuminates a key role for these kinases in alveolar bone biology and highlights the emerging concept that different osteoblast subsets utilize unique genetic programs. Summary statementSIK2/SIK3 deletion in alveolar bone reduces bone formation and mass by impairing osteoblast maturation, unlike in long bones, where it increases bone formation and mass.

developmental biology↗

bioRxiv2023

Growth plate resting zone chondrocytes acquire transient clonal competency upon Hedgehog activation and efficiently transform into trabecular bone osteoblasts

The resting zone of the postnatal growth plate is organized by slow-cycling chondrocytes expressing parathyroid hormone-related protein (PTHrP), which include a subgroup of skeletal stem cells that contribute to the formation of columnar chondrocytes. The PTHrP-indian hedgehog (Ihh) feedback regulation is essential for sustaining growth plate activities; however, molecular mechanisms regulating cell fates of PTHrP+ resting chondrocytes and their eventual transformation into osteoblasts remain largely undefined. Here, in a mouse model, we utilized a tamoxifen-inducible PTHrP-creER line with Patched-1 (Ptch1) floxed and tdTomato reporter alleles to specifically activate Hedgehog signaling in PTHrP+ resting chondrocytes and trace the fate of their descendants. Hedgehog-activated PTHrP+ chondrocytes formed large concentric clonally expanded cell populations within the resting zone ( patched roses) and generated significantly wider columns of chondrocytes, resulting in hyperplasia of the growth plate. Interestingly, Hedgehog-activated PTHrP+ cell-descendants migrated away from the growth plate and eventually transformed into trabecular osteoblasts in the diaphyseal marrow space in the long term. Therefore, Hedgehog activation drives resting zone chondrocytes into transit-amplifying states as proliferating chondrocytes and eventually converts these cells into osteoblasts, unraveling a novel Hedgehog-mediated mechanism that facilitates osteogenic cell fates of PTHrP+ skeletal stem cells.

developmental biology↗

bioRxiv2020

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

Chondrocytes in the resting zone of the postnatal growth plate are characterized by slow cell cycle progression, and encompass a population of parathyroid hormone-related protein (PTHrP)-expressing skeletal stem cells that contribute to the formation of columnar chondrocytes. However, how these chondrocytes are maintained in the resting zone remains undefined. We undertook a genetic pulse-chase approach to isolate slow cycling, label-retaining chondrocytes (LRCs) from the growth plate using a chondrocyte-specific doxycycline-controllable Tet-Off system regulating expression of histone 2B-linked GFP. Comparative RNA-seq analysis identified significant enrichment of inhibitors and activators for Wnt/{beta}-catenin signaling in LRCs and non-LRCs, respectively. Activation of Wnt/{beta}-catenin signaling in PTHrP+ resting chondrocytes using Pthrp-creER and Apc-floxed allele impaired their ability to form columnar chondrocytes. Therefore, slow-cycling chondrocytes are maintained in a canonical Wnt-inhibitory environment within the resting zone, unraveling a novel mechanism regulating maintenance and differentiation of PTHrP+ skeletal stem cells of the postnatal growth plate.

developmental biology↗

bioRxiv2020

Notch effector Hes1 marks an early perichondrial population of skeletal progenitor cells at the onset of endochondral bone development

The perichondrium, a fibrous tissue surrounding the fetal cartilage, is an essential component of developing endochondral bones that provides a source of skeletal progenitor cells. However, perichondrial cells remain poorly characterized due to lack of knowledge on their cellular diversity and subset-specific mouse genetics tools. Single cell RNA-seq analyses reveal a contiguous nature of the fetal chondrocyte-perichondrial cell lineage that shares an overlapping set of marker genes. Subsequent cell-lineage analyses using multiple creER lines active in fetal perichondrial cells - Hes1-creER, Dlx5-creER - and chondrocytes - Fgfr3-creER - illustrate their distinctive contribution to endochondral bone development; postnatally, these cells contribute to the functionally distinct bone marrow stromal compartments. Particularly, Notch effector Hes1-creER marks an early skeletal progenitor cell population in the primordium that robustly populates multiple skeletal compartments. These findings support the concept that perichondrial cells participate in endochondral bone development through a distinct route, by providing a complementary source of skeletal progenitor cells.

developmental biology↗