Hypoxia affected SDF-1alpha-CXCR4 interaction between bone marrow stem cells and osteoblasts via osteoclast modulation.

摘要

Osteoclasts (OCLs) are bone-resorbing multinucleated cells derived from macrophage-monocyte lineage progen itors. These tissue-specific, specialized cells require re ceptor activator of nuclear factor-kappaB ligand (RANKL) sig nals from osteoblasts (OBs) for their proliferation, differ entiation and bone-resorbing activity. Responding to RANKL stimulation, bone marrow (BM) OCL precursors become functional OCLs and play a central role in the regulation of bone mass along with bone-forming OBs [1]. Recently, it was reported that OCLs can lead to stem cell mobilization as a novel component of a stem cell niche in the BM. In mammals, BM composed mainly of hemato-poietic stem cells (HSCs) is encased within the bone struc ture. A portion of these hematopoietic cells, classified as an osteoblastic niche, can be found next to the endosteal bone surface, a surface lined primarily by OBs [2]. This anatomical arrangement makes it possible for reciprocal communication between the two cell types. To maintain physiological homeostasis, the niche orchestrates a myri ad of signaling and adhesive interactions through the linkage between stem cell factor/c-Kit, Jagged/Notch, an-giopoietin-l/Tie2, and Ca~(2+)-sensing receptor [3]. All of the cell surface receptors for these signals have been found on HSCs, and their respective ligands are mostly expressed by osteoblastic cells of the endosteal bone niche. Ligation of these receptors and ligands maintains the adhesive in teraction of the steady state; however, under stress situa tions such as inflammation, injury and hypoxia, these bal ances are broken and HSCs are mobilized into the blood stream [4]. During this process, OCLs play a role in the enzymatic cleavage of the linkage between OBs and HSCs. OCLs activated by stress-induced signals secrete proteo-lytic enzymes such as matrix metalloproteinase 9 (MMP9) and cathepsin K (CTK) that are responsible for the degra dation of bone mineral and collagen matrix. These en zymes trigger weakness in the OBs-HSCs anchorage and ultimately lead to the mobilization of stem cells into cir culation. Among the molecules which might be weakened by OCLs in the osteoblastic niche, we focused on SDF-1alpha, a molecule expressed on OBs and its cognitive receptor, CXCR4, expressed on the HSCs [5]. SDF-la, the most well-known powerful stem cell chemoattractant, is a stem cell survival factor and also a regulator of interactions fa cilitating the adhesion between stem cells and the extra cellular matrix or stromal cells [6]. These observations in dicate that the SDF-la-CXCR4 axis may be involved in regulating the HSCs residence in niche.