Extracellular matrix proteoglycans control the fate of bone marrow stromal cells.
Extracellular matrix glycoproteins and proteoglycans bind a variety of growth factors and cytokines thereby regulating matrix assembly as well as bone formation. However, little is known about the mechanisms by which extracellular matrix molecules modulate osteogenic stem cells and bone formation. Using mice deficient in two members of the small leucine-rich proteoglycans, biglycan and decorin, we uncovered a role for these two extracellular matrix proteoglycans in modulating bone formation from bone marrow stromal cells. Our studies showed that the absence of the critical transforming growth factor-beta (TGF-beta)-binding proteoglycans, biglycan and decorin, prevents TGF-beta from proper sequestration within the extracellular matrix. The excess TGF-beta directly binds to its receptors on bone marrow stromal cells and overactivates its signaling transduction pathway. Overall, the predominant effect of the increased TGF-beta signaling in bgn/dcn-deficient bone marrow stromal cells is a "switch in fate" from growth to apoptosis, leading to decreased numbers of osteoprogenitor cells and subsequently reduced bone formation. Thus, biglycan and decorin appear to be essential for maintaining an appropriate number of mature osteoblasts by modulating the proliferation and survival of bone marrow stromal cells. These findings underscore the importance of the micro-environment in controlling the fate of adult stem cells and reveal a novel cellular and molecular basis for the physiological and pathological control of bone mass.
Bi
Yanming
Y
Craniofacial and Skeletal Diseases Branch, NIDCR, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA.
Stuelten
Christina H
CH
Kilts
Tina
T
Wadhwa
Sunil
S
Iozzo
Renato V
RV
Robey
Pamela G
PG
Chen
Xiao-Dong
XD
Young
Marian F
MF
D000818:Animals; D017209:Apoptosis; D058578:Biglycan; D015152:Blotting, Northern; D015153:Blotting, Western; D015519:Bone Density; D001854:Bone Marrow Cells / Q000166:cytology*; D001842:Bone and Bones / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D019070:Cell Lineage; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D003470:Culture Media; D058575:Decorin; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008809:Mice, Inbred C3H; D018613:Microscopy, Confocal; D010006:Osteoblasts / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000473:pathology; D017154:Stromal Cells / Q000166:cytology* / Q000378:metabolism; D014057:Tomography, X-Ray Computed; D016212:Transforming Growth Factor beta / Q000378:metabolism
C546884:BGN protein, human; C546885:Bgn protein, mouse; D058578:Biglycan; D003470:Culture Media; C546878:DCN protein, human; C546879:Dcn protein, mouse; D058575:Decorin; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D016212:Transforming Growth Factor beta; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases