Abstract
Factors mediating mobilization of osteoblastic stem and progenitor cells from their bone marrow niche to be recruited to bone formation sites during bone remodeling are poorly known. We have studied secreted factors present in the bone marrow microenvironment and identified KIAA1199 (also known as CEMIP, cell migration inducing hyaluronan binding protein) in human bone biopsies as highly expressed in osteoprogenitor reversal cells (Rv.C) recruited to the eroded surfaces (ES), which are the future bone formation sites. In vitro, KIAA1199 did not affect the proliferation of human osteoblastic stem cells (also known as human bone marrow skeletal or stromal stem cells, hMSCs); but it enhanced cell migration as determined by scratch assay and trans-well migration assay. KIAA1199 deficient hMSCs (KIAA1199down) exhibited significant changes in cell size, cell length, ratio of cell width to length and cell roundness, together with reduction of polymerization actin (F-actin) and changes in phos-CFL1 (cofflin1), phos-LIMK1 (LIM domain kinase 1) and DSTN (destrin), key factors regulating actin cytoskeletal dynamics and cell motility. Moreover, KIAA1199down hMSC exhibited impaired Wnt signaling in TCF-reporter assay and decreased expression of Wnt target genes and these effects were rescued by KIAA1199 treatment. Finally, KIAA1199 regulated the activation of P38 kinase and its associated changes in Wnt-signaling. Thus, KIAA1199 is a mobilizing factor that interacts with P38 and Wnt signaling, and induces changes in actin cytoskeleton, as a mechanism mediating recruitment of hMSC to bone formation sites.
Highlights
Human osteoprogenitor cells, known as human skeletal stem cells, marrow stromal or mesenchymal stem cells, represent a population of nonhematopoietic cells that exist at different locations within the bone marrow near eroded surfaces and can differentiate into mature osteoblastic bone forming cells[1,2]
Our previous study had identified KIAA1199 as a secreted factor by human osteoblastic stem cells, and its secretion is enhanced during osteoblast differentiation in vitro[15]
To corroborate the cellular expression of KIAA1199 in the bone marrow microenvironment in vivo, we performed in situ hybridization analysis of adult human iliac crest bone biopsies that revealed KIAA1199 expression was localized to bone formation sites during bone remodeling and expressed in immature and mature osteoblastic cells along bone surfaces in both cancellous and cortical bone (Fig. 1)
Summary
Known as human skeletal stem cells, marrow stromal or mesenchymal stem cells (hMSCs), represent a population of nonhematopoietic cells that exist at different locations within the bone marrow near eroded surfaces and can differentiate into mature osteoblastic bone forming cells[1,2]. The initiation of in vivo bone formation during skeletal remodeling and bone regeneration during fracture healing depend on the mobilization of sufficient number of osteoprogenitor cells to future bone formation sites[1]. As bone remodeling takes place asynchronously in the skeleton, the coupling of bone formation to resorption is tightly orchestrated by local coupling factors. These coupling factors are believed to mobilize osteoprogenitor cells from their niche, and recruit them to eroded surface prior to initiation of bone formation[1]. The identity of these factors is under investigation and currently only few have been identified and shown to be produced by osteoclastic, osteoblastic cells or other cells in the hematopoietic microenvironment[4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
