Abstract
Bone marrow stromal cells maintain the adult skeleton by forming osteoblasts throughout life that regenerate bone and repair fractures. We discovered that subsets of these stromal cells, osteoblasts, osteocytes, and hypertrophic chondrocytes secrete a C-type lectin domain protein, Clec11a, which promotes osteogenesis. Clec11a-deficient mice appeared developmentally normal and had normal hematopoiesis but reduced limb and vertebral bone. Clec11a-deficient mice exhibited accelerated bone loss during aging, reduced bone strength, and delayed fracture healing. Bone marrow stromal cells from Clec11a-deficient mice showed impaired osteogenic differentiation, but normal adipogenic and chondrogenic differentiation. Recombinant Clec11a promoted osteogenesis by stromal cells in culture and increased bone mass in osteoporotic mice in vivo. Recombinant human Clec11a promoted osteogenesis by human bone marrow stromal cells in culture and in vivo. Clec11a thus maintains the adult skeleton by promoting the differentiation of mesenchymal progenitors into mature osteoblasts. In light of this, we propose to call this factor Osteolectin.
Highlights
IntroductionFate mapping studies in vivo show there are multiple distinct waves of mesenchymal progenitors that form skeletal tissues during development and maintain the skeleton throughout adulthood (Liu et al, 2013; Maes et al, 2010; Mizoguchi et al, 2014; Park et al, 2012; Takashima et al, 2007; Worthley et al, 2015; Zhou et al, 2014a)
Clec11a was expressed by subsets of bone marrow stromal cells, osteoblasts, osteocytes, and hypertrophic chondrocytes, in the metaphysis, and in portions of cortical bone (Figure 1)
In light of the unanticipated osteogenic activity of Clec11a, and its role in the maintenance of the adult skeleton, we propose to call this growth factor Osteolectin, a name that is more descriptive of both biological function and protein structure
Summary
Fate mapping studies in vivo show there are multiple distinct waves of mesenchymal progenitors that form skeletal tissues during development and maintain the skeleton throughout adulthood (Liu et al, 2013; Maes et al, 2010; Mizoguchi et al, 2014; Park et al, 2012; Takashima et al, 2007; Worthley et al, 2015; Zhou et al, 2014a) These include Osterix+ cells that give rise to osteoblasts, osteocytes, and stromal cells in developing bones (Liu et al, 2013; Maes et al, 2010; Mizoguchi et al, 2014), Nestin-CreER-expressing cells that transiently form osteoblasts and bone marrow stromal cells in the early postnatal period (Mendez-Ferrer et al, 2010; Ono et al, 2014a; Takashima et al, 2007), Grem1-expressing cells that form osteoblasts, chondrocytes, and stromal cells postnatally (Worthley et al, 2015) and Leptin Receptor (LepR)-expressing stromal cells that are the major source of bone and adipocytes in adult mouse bone marrow (Mizoguchi et al, 2014; Zhou et al, 2014a).
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