KIAA1199 deficiency enhances skeletal stem cell differentiation to osteoblasts and promotes bone regeneration

Li Chen (), Kaikai Shi, Nicholas Ditzel, Weimin Qiu, Florence Figeac, Louise Himmelstrup Dreyer Nielsen, Michaela Tencerova, Justyna Magdalena Kowal, Ming Ding, Christina Møller Andreasen, Thomas Levin Andersen and Moustapha Kassem ()
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Li Chen: Odense University Hospital & University of Southern Denmark
Kaikai Shi: Odense University Hospital & University of Southern Denmark
Nicholas Ditzel: Odense University Hospital & University of Southern Denmark
Weimin Qiu: Odense University Hospital & University of Southern Denmark
Florence Figeac: Odense University Hospital & University of Southern Denmark
Louise Himmelstrup Dreyer Nielsen: Odense University Hospital & University of Southern Denmark
Michaela Tencerova: Odense University Hospital & University of Southern Denmark
Justyna Magdalena Kowal: Odense University Hospital & University of Southern Denmark
Ming Ding: Odense University Hospital & University of Southern Denmark
Christina Møller Andreasen: University of Southern Denmark
Thomas Levin Andersen: University of Southern Denmark
Moustapha Kassem: Odense University Hospital & University of Southern Denmark

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Upon transplantation, skeletal stem cells (also known as bone marrow stromal or mesenchymal stem cells) can regulate bone regeneration by producing secreted factors. Here, we identify KIAA1199 as a bone marrow stromal cell-secreted factor in vitro and in vivo. KIAA1199 plasma levels of patients positively correlate with osteoporotic fracture risk and expression levels of KIAA1199 in patient bone marrow stromal cells negatively correlates with their osteogenic differentiation potential. KIAA1199-deficient bone marrow stromal cells exhibit enhanced osteoblast differentiation in vitro and ectopic bone formation in vivo. Consistently, KIAA1199 knockout mice display increased bone mass and biomechanical strength, as well as an increased bone formation rate. They also exhibit accelerated healing of surgically generated bone defects and are protected from ovariectomy-induced bone loss. Mechanistically, KIAA1199 regulates osteogenesis by inhibiting the production of osteopontin by osteoblasts, via integrin-mediated AKT and ERK-MAPK intracellular signaling. Thus, KIAA1199 is a regulator of osteoblast differentiation and bone regeneration and could be targeted for the treatment or management of low bone mass conditions.

Date: 2023
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DOI: 10.1038/s41467-023-37651-1

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