ESPEYB20 3. Bone, Growth Plate and Mineral Metabolism Advances in Growth, Bone Biology, and Mineral Metabolism (6 abstracts)
3.18. Periosteal stem cells control growth plate stem cells during postnatal skeletal growth
Tsukasaki M , Komatsu N , Negishi-Koga T , Huynh NC , Muro R , Ando Y , Seki Y , Terashima A , Pluemsakunthai W , Nitta T , Nakamura T , Nakashima T , Ohba S , Akiyama H , Okamoto K , Baron R & Takayanagi H
Nat Commun. 2022 Jul 18;13(1):4166. doi: 10.1038/s41467-022-31592-x 10.1038/s41467-022-31592-x. PMID: 35851381. https://pubmed.ncbi.nlm.nih.gov/35851381/
In Brief: The authors use cell tracing approaches in a PRMT5flox/Δ Ctsk-Cre strain to label periosteal stem cells (PSCs) and show that PSCs are not only essential for intramembranous bone formation but also for endochondral bone formation. The study identifies the role of PSC derived indian hedgehog (Ihh) in maintaining growth plate homeostasis and postnatal skeletal growth.
Commentary: The skeleton harbors stem cells in three independent niches: the growth plate resting zone, the periosteum/perichondrium, and the bone marrow. Periosteal stem cells (PSCs) were identified recently and shown to play a role in intramembranous bone formation. In this study, PSCs were shown to be important for endochondral bone formation through the secretion of Ihh.
While studying the role of the enzyme protein arginine methyltransferase 5 (PRMT5) in osteoclastogenesis, the authors generated a mouse strain (PRMT5flox/Δ Ctsk-Cre) wherein cre enzyme is expressed in osteoclasts as well as PSCs. These mice showed reduced bone volume, calvarial volume and abnormal growth plate architecture with reduced column length suggesting defective intramembranous and endochondral bone formation. The altered skeletal phenotype became prominent with aging. Using a well-defined FACS gating strategy, the authors isolated PSCs from these mice and found that the number of PSCs were markedly reduced. The role of PSCs ablation in endochondral bone formation was confirmed by studying diptheria toxin mediated selective depletion of Ctsk+ cells. The resulting mice had reduced body size, bone length, bone width and trabecular bone volume. Further, the authors specifically ablated Ihh in PSCs (Ihh flox/flox x Ctsk-Cre) and found that these mice had reduced body size, bone length and body weight, indicating that endochondral bone formation was indeed affected. The phenotype was not evident until 3 weeks of age but manifested strongly as the animals became older and displayed complete loss of trabecular bone at 11 weeks of age. Additionally, both calvarial bone volume and bone width were decreased in these animals indicating that intramembranous ossification was also affected.
These findings show that PSCs are essential for both intramembranous and endochondral bone formation. In contrast to the role of Ihh/PTHrP in maintaining chondrocyte proliferation by regulating the fate of resting zone stem cells during early development, PSC-derived Ihh acts on resting zone stem cells to maintain postnatal skeletal growth. The study therefore establishes a functional link between periosteal stem cells and growth plate resting zone stem cells and further shows that both intramembranous and endochondral ossification processes co-operate to ensure proper bone development and maintenance.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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