ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2020) 17 5.12 | DOI: 10.1530/ey.17.5.12

ESPEYB17 5. Bone, Growth Plate and Mineral Metabolism Advances in Skeletal Biology (4 abstracts)

5.12. Lipid availability determines fate of skeletal progenitor cells via SOX9

van Gastel N, Stegen S, Eelen G, Schoors S, Carlier A, Daniëls VW, Baryawno N, Przybylski D, Depypere M, Stiers PJ, Lambrechts D, Van Looveren R, Torrekens S, Sharda A, Agostinis P, Lambrechts D, Maes F, Swinnen JV, Geris L, Van Oosterwyck H, Thienpont B, Carmeliet P, Scadden DT & Carmeliet G


Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium


To read the full abstract: Nature 2020;579:111–117.

In brief: In large fracture calluses, skeletal progenitors activate the chondrogenesis program, whereas in smaller calluses, direct osteogenesis is the preferred path. Here, the authors show that lipid availability determines whether skeletal stem cells repair a fracture through endochondral bone formation or direct ossification.

Commentary: Fracture repair reiterates normal skeletal development and is initiated by skeletal progenitor cells at the fracture site, which proliferate, condensate and differentiate into chondrocytes that form an avascular cartilage template which is then remodelled into bone. However, in the event of a small fracture or crack, the skeletal stem cells do not differentiate into chondrocytes, but instead directly to osteoblasts which repair the fracture through direct bone formation. The determinants of skeletal stem cell differentiation into chondrocytes or osteoblasts at fractures sites have not been previously determined.

The authors first show in vivo that the lack of vasculature in large calluses is associated with chondrogenic differentiation, whereas small calluses have abundant vasculature and that blocking vasculature in-growth in small calluses leads to chondrogenic, rather than osteogenic differentiation. They next culture skeletal stem cells under different conditions and demonstrate that a large part of the chondrogenic effect of serum deprivation is reproduced by culturing skeletal stem cells in media deprived of lipids, and that skeletal progenitors cultured under lipid scarce conditions activate forkhead box O (FOXO) transcription factors, which bind to the SOX9 promoter and increase its expression. Besides initiating chondrogenesis, SOX9 acts as a regulator of cellular metabolism by suppressing oxidation of fatty acids, and thus adapts the cells to an avascular life.

These findings define lipids as a critical determinant of chondrogenic commitment, revealing a role for FOXO transcription factors during lipid starvation and identify SOX9 as a critical metabolic mediator. These data demonstrate the bone regulatory role of lipids and highlight the importance of the nutritional microenvironment in the specification of skeletal cell fate.

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