Generation of Novel Bone Forming Cells (Monoosteophils) from the Cathelicidin-Derived Peptide LL-37 Treated Monocytes 英文参考文献.docVIP

GenerationofNovelBoneFormingCells(Monoosteophils) fromtheCathelicidin-DerivedPeptideLL-37Treated Monocytes ZhifangZhang,JohnE.Shively* DepartmentofImmunology,BeckmanResearchInstituteoftheCityofHope,Duarte,California,UnitedStatesofAmerica Abstract Background: Bone generation and maintenance involve osteoblasts, osteoclasts, and osteocytes which originate from unique precursors and rely on key growth factors for differentiation. However, an incomplete understanding of bone formingcellsduringwoundhealinghasledtoanunfilledclinicalneedsuchasnonunionofbonefractures.Sincecirculating monocytes are often recruited to sites of injury and may differentiate into various cell types including osteoclasts, we investigatedthepossibilitythatcirculatingmonocytesinthecontextoftissueinjurymayalsocontributetobonerepair.In particular,wehypothesizedthatLL-37(producedfromhCAP-18,cathelicidin),whichrecruitscirculatingmonocytesduring injury,mayplayaroleinbonerepair. MethodsandFindings:TreatmentofmonocytesfrombloodwithLL-37for6daysresultedintheirdifferentiationtolarge adherent cells. Growth of LL-37-differentiated monocytes on osteologic discs reveals bone-like nodule formation by scanning electron microscopy (SEM). In vivo transplantation studies in NOD/SCID mice show that LL-37-differentiated monocytesformbone-likestructuressimilartoendochondralboneformation.Importantly,LL-37-differentiatedmonocytes aredistinctfromconventionalmonocyte-derivedosteoclasts,macrophages,anddendriticcellsanddonotexpressmarkers of the mesenchymal stem cells (MSC) lineage, distinguishing them from the conventional precursors of osteoblasts. Furthermore, LL-37 differentiated monocytes express intracellular proteins of both the osteoblast and osteoclast lineage includingosteocalcin(OC),osteonectin(ON),bonesialoproteinII(BSPII),osteopontin(OP),RANK,RANKL,MMP-9,tartrate resistantacidphosphatase(TRAP),andcathepsinK(CK). Conclusion:BloodderivedmonocytestreatedwithLL-37canbedifferentiatedintoanovelboneformingcellthatfun