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

Abstract

We previously discovered a new osteogenic growth factor that is required to maintain adult skeletal bone mass, Osteolectin/Clec11a. Osteolectin acts on Leptin Receptor ⁺ (LepR ⁺) skeletal stem cells and other osteogenic progenitors in bone marrow to promote their differentiation into osteoblasts. Here we identify a receptor for Osteolectin, integrin α11, which is expressed by LepR ⁺ cells and osteoblasts. α11β1 integrin binds Osteolectin with nanomolar affinity and is required for the osteogenic response to Osteolectin. Deletion of Itga11 (which encodes α11) from mouse and human bone marrow stromal cells impaired osteogenic differentiation and blocked their response to Osteolectin. Like Osteolectin deficient mice, Lepr-cre; Itga11 ^fl/fl mice appeared grossly normal but exhibited reduced osteogenesis and accelerated bone loss during adulthood. Osteolectin binding to α11β1 promoted Wnt pathway activation, which was necessary for the osteogenic response to Osteolectin. This reveals a new mechanism for maintenance of adult bone mass: Wnt pathway activation by Osteolectin/α11β1 signaling.

eLife digest

Throughout our lives, our bones undergo constant remodeling. Cells called osteoclasts break down old bone and cells called osteoblasts lay down new. Normally, the two cell types work in balance but if the rate of breakdown outpaces new bone formation the skeleton can become weak. This weakness leads to a condition called osteoporosis, in which people suffer from fragile bones. Osteoporosis is hard to reverse, in part because our ability to encourage new bone to form is limited.

In 2016, researchers discovered a protein called osteolectin, which promotes new bone formation during adulthood by helping skeletal stem cells transform into bone cells. But so far, it has been unclear how osteolectin achieves this. To investigate this further, Shen et al. – including some researchers involved in the 2016 study – marked osteolectin with a molecular tag and tested what it bound on the surface of mouse and human bone marrow cells.

The experiments revealed that osteolectin binds to a specific receptor protein called α11 integrin, which can only be found on skeletal stem cells and the osteoblasts they give rise to. Once osteolectin binds to the receptor, it activates a signaling pathway that induces the stem cells to develop into osteoblasts. Mice that lacked either osteolectin or α11 integrin produced less bone and lost bone tissue faster as adults.

Osteolectin could potentially be useful in the treatment of osteoporosis or broken bones. Since only skeletal stem cells and osteoblasts cells produce α11 integrin, osteolectin would specifically target these cells without affecting cells that do not form bones. A next step will be to assess how well osteolectin compares to existing treatments for fragile bones.