Different effects of BMP-2 on marrow stromal cells from human and rat bone.
Bone morphogenetic proteins (BMPs) promote the differentiation of osteoprogenitor cells, and also induce osteogenesis in bone marrow stromal cells (MSC) from rats and mice. However, compared to results with animal models, BMPs are relatively inefficient in inducing human MSC to undergo osteogenesis, and are much less effective in promoting bone formation in human clinical trials. Previous studies indicated that, while human MSC respond to dexamethasone with elevated levels of the osteoblast marker alkaline phosphatase, most isolates of human MSC fail to show alkaline phosphatase induction in response to BMP-2, BMP-4, or BMP-7. Several other genes known to be induced by BMPs are appropriately regulated; thus, human MSC are capable of some BMP-activated signaling. Analysis of the BMP receptors ALK-3 and ALK-6 indicated that, although ALK-6 mRNA was not expressed in human MSC, overexpressing a constitutively active ALK-6 receptor did not induce elevated alkaline phosphatase. Real-time RT-PCR was used to investigate expression of several osteoblast-related transcription factors in MSC after 6 days' exposure to BMP2 or dexamethasone. Msx-2, a transcription factor that has been reported to inhibit differentiation of osteoprogenitor cells, showed 10-fold elevation in BMP-2-treated human MSC, but not in BMP-2-treated rat MSC. Overexpression of Msx-2 in human and rat MSC, however, did not alter alkaline phosphatase levels, which suggests that absence of BMP-stimulated alkaline phosphatase was not caused by the BMP-2-induced increase in Msx-2. Although Runx2 isoforms have been implicated in control of osteoblast differentiation, levels of this transcription factor were unaffected by BMP treatment. Expression of the FKHR transcription factor, which has been reported to regulate alkaline phosphatase transcription in mouse cells, showed a modest increase in response to BMP-2, but a much greater increase in dexamethasone-treated cells. We propose that BMP regulation of the bone/liver/kidney alkaline phosphatase gene is indirect, requiring expression of new transcription factor(s) that behave differently in rodent and human MSC.
Osyczka
Anna M
AM
Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pa., USA.
Diefenderfer
David L
DL
Bhargave
Geeta
G
Leboy
Phoebe S
PS
D000328:Adult; D000368:Aged; D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism*; D055396:Bone Morphogenetic Protein 2; D052005:Bone Morphogenetic Protein Receptors, Type I; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D002352:Carrier Proteins; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005269:Femur / Q000166:cytology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1; D008297:Male; D051379:Mice; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins; D010006:Osteoblasts / Q000737:chemistry / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011506:Proteins / Q000235:genetics; D051381:Rats; D017978:Receptors, Growth Factor / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein
D000469:Alkaline Phosphatase; D055396:Bone Morphogenetic Protein 2; D052005:Bone Morphogenetic Protein Receptors, Type I; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins; D003907:Dexamethasone; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D051798:Inhibitor of Differentiation Protein 1; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D017978:Receptors, Growth Factor; D012097:Repressor Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein; C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; C525720:Bmp2 protein, rat; C085126:FOXO1 protein, human; C467200:Foxo1 protein, mouse; C497453:ID1 protein, human; C497454:ID1 protein, rat; C497455:Idb1 protein, mouse; C084119:MSX2 protein; C074639:Foxo1 protein, rat; C498212:Bmpr1a protein, mouse; C498213:Bmpr1a protein, rat; C498216:Bmpr1b protein, rat