Clec11a/osteolectin is an osteogenic growth factor that promotes the maintenance of the adult skeleton

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.DOI: http://dx.doi.org/10.7554/eLife.18782.001

Integrin alpha11 is an Osteolectin receptor and is required for the maintenance of adult skeletal bone mass

“…Prior studies had observed Clec11a expression in bone marrow but inferred based on colony-forming assays in culture that it was a hematopoietic growth factor (Hiraoka et al, 1997;Hiraoka et al, 2001). We made germline knockout mice and found it is not required for normal hematopoiesis but that it is required for the maintenance of the adult skeleton (Yue et al, 2016). The mutant mice formed their skeleton normally during development and were otherwise grossly normal as adults but exhibited reduced adult osteogenesis and accelerated bone loss during aging (Yue et al, 2016).…”

“…To identify new growth factors that regulate hematopoiesis or osteogenesis, we performed RNA-Seq analysis on LepR + cells and looked for transcripts predicted to encode secreted proteins with sizes and structures similar to growth factors and whose function had not been studied in vivo. We discovered that Clec11a, a secreted glycoprotein of the C-type lectin domain superfamily (Bannwarth et al, 1999;Bannwarth et al, 1998), was preferentially expressed by LepR + cells (Yue et al, 2016). Prior studies had observed Clec11a expression in bone marrow but inferred based on colony-forming assays in culture that it was a hematopoietic growth factor (Hiraoka et al, 1997;Hiraoka et al, 2001).…”

“…We made germline knockout mice and found it is not required for normal hematopoiesis but that it is required for the maintenance of the adult skeleton (Yue et al, 2016). The mutant mice formed their skeleton normally during development and were otherwise grossly normal as adults but exhibited reduced adult osteogenesis and accelerated bone loss during aging (Yue et al, 2016). Recombinant protein promoted osteogenic differentiation by bone marrow stromal cells in vitro and in vivo (Yue et al, 2016).…”

Phenotypic characterization of Slc26a2 mutant mice reveals a multifactorial etiology of spondylolysis

“…34 [ 35 S]UTP-labeled riboprobes used in this study were as follows: Col2a1, 34 Pthr1, 35 Col10a1, and MMP13. 37 Mineral apposition rate was measured as previously described.…”

Lectins bring benefits to bones

“…Examples of c-type lectins include thrombomodulin, which regulates platelet-dependent coagulation, and selectins, which control the movement of white blood cells during inflammation (Cummings et al, 2009). Now, in eLife, Rui Yue, Bo Shen and Sean Morrison at the University of Texas Southwestern Medical Center report that Clec11a, a type of c-lectin that is expressed at high levels by cells in bone marrow, stimulates bone regeneration (Yue et al, 2016). …”