Abstract
BackgroundAn incomplete understanding of bone forming cells during wound healing and ectopic calcification has led to a search for circulating cells that may fulfill this function. Previously, we showed that monoosteophils, a novel lineage of calcifying/bone-forming cells generated by treatment of monocytes with the natural peptide LL-37, are candidates. In this study, we have analyzed their gene expression profile and bone repair function.Methods and FindingsHuman monoosteophils can be distinguished from monocytes, macrophages and osteoclasts by their unique up-regulation of integrin α3 and down-regulation of CD14 and CD16. Monoosteophils express high mRNA and protein levels of SPP1 (osteopontin), GPNMB (osteoactivin), CHI3L1 (cartilage glycoprotein-39), CHIT1 (Chitinase 1), MMP-7, CCL22 and MAPK13 (p38MAPKδ). Monocytes from wild type, but not MAPK13 KO mice are also capable of monoosteophil differentiation, suggesting that MAPK13 regulates this process. When human monoosteophils were implanted in a freshly drilled hole in mid-diaphyseal femurs of NOD/SCID mice, significant bone repair required only 14 days compared to at least 24 days in control treated injuries.ConclusionHuman derived monoosteophils, characterized as CD45+α3+α3β+CD34−CD14−BAP (bone alkaline phosphatase)− cells, can function in an animal model of bone injury.
Highlights
Bone generation, maintenance and repair involve osteoblasts, osteoclasts, and osteocytes
scanning electron microscopy (SEM)/energy dispersive X-ray spectroscopy (EDS) Analysis of Monoosteophil-formed Nodules We previously showed that monoosteophils built refractive, raised granules on the surface of osteologic discs that were identified as inorganic phosphate deposits by von Kossa staining [12]
In order to verify that the deposits were mineralized calcium phosphate, we used scanning electron microscopy (SEM) coupled with an energy dispersive X-ray spectroscopy (EDS) analyzer to investigate the elemental composition of the granules
Summary
Maintenance and repair involve osteoblasts, osteoclasts, and osteocytes. Osteoblasts are cells of mesenchymal stem cell (MSC) origin that secrete bone-matrix proteins and promote mineralization. Differentiated osteoblasts embedded in the bone matrix or osteocytes have an as-yet unclear role in mechanotransduction [1]. Osteoclasts are cells of hematopoietic origin that decalcify and degrade the bone matrix by acid decalcification and proteolytic degradation. They are large, multinucleated cells formed by the fusion of precursor cells of the monocyte–macrophage lineage. We showed that monoosteophils, a novel lineage of calcifying/bone-forming cells generated by treatment of monocytes with the natural peptide LL-37, are candidates. We have analyzed their gene expression profile and bone repair function
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