The cell cycle regulator p27kip1 contributes to growth and differentiation of osteoblasts.
The cyclin-dependent kinase (cdk) inhibitors are key regulators of cell cycle progression. p27 and p21 are members of the Cip/Kip family of cdk inhibitors and regulate cell growth by inactivating cell cycle stage-specific CDK-cyclin complexes. Because down-regulation of osteoprogenitor proliferation is a critical step for osteoblast differentiation, we investigated expression of p27 and p21 during development of the osteoblast phenotype in rat calvarial osteoblasts and in proliferating and growth-inhibited osteosarcoma ROS 17/2.8 cells. Expression of these proteins indicates that p21, which predominates in the growth period, is related to proliferation control. p27 levels are maximal postproliferatively, suggesting a role in the transition from cell proliferation to osteoblast differentiation. We directly examined the role of p27 during differentiation of osteoprogenitor cells derived from the bone marrow (BM) of p27-/- mice. BM cells from p27 null mice exhibited increased proliferative activity compared with BM cells from wild-type mice and formed an increased number and larger size of osteoblastic colonies, which further differentiated to the mineralization stage. Although p27-/- adherent marrow cells proliferate faster, they retain competency for differentiation, which may result, in part, from observed higher p21 levels compared with wild type. Histological studies of p27-/- bones also showed an increased cellularity in the marrow cavity compared with the p27+/+. The increased proliferation in bone does not lead to tumorigenesis, in contrast to observed adenomas in the null mice. Taken together, these findings indicate that p27 plays a key role in regulating osteoblast differentiation by controlling proliferation-related events in bone cells.
Drissi
H
H
Department of Cell Biology, University of Massachusetts Medical School, Worcester 01655, USA.
Hushka
D
D
Aslam
F
F
Nguyen
Q
Q
Buffone
E
E
Koff
A
A
van Wijnen
A
A
Lian
J B
JB
Stein
J L
JL
Stein
G S
GS
D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology; D002113:Calcification, Physiologic; D002118:Calcium / Q000032:analysis; D002452:Cell Count; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000502:physiology; D004247:DNA / Q000032:analysis; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D010006:Osteoblasts / Q000166:cytology*; D012516:Osteosarcoma / Q000473:pathology; D051381:Rats; D012886:Skull / Q000166:cytology / Q000196:embryology; D017154:Stromal Cells / Q000166:cytology; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
C493957:Cdkn1a protein, mouse; C493958:Cdkn1a protein, rat; C493961:Cdkn1b protein, mouse; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA; D002118:Calcium