title: Platelet-derived growth factor enhances bone cell replication, but not differentiated function of osteoblasts.
abstract: Platelet-derived growth factor (PDGF), a polypeptide mitogen, is a dimer composed of PDGF-AA and -BB chains. In rats, PDGF-BB is the prevalent circulating form, whereas in bone, PDGF-AA is the isoform secreted by unstimulated normal bone cells. Although PDGF-BB increased DNA synthesis in fetal rat calvariae, the effects on collagen synthesis were small and inconsistent. To localize the cells in the cranial periosteum that were responding to PDGF isoforms AA and BB, we cultured 21-day-old fetal rat calvariae to assess the effects of human recombinant PDGF-AA and -BB on bone cell replication and matrix formation. Changes were assessed using histomorphometry and autoradiography and correlated with effects on collagen synthesis and [3H]thymidine incorporation, using biochemical assays. PDGF-AA and -BB at 0.03-3.3 nM (1-100 ng/ml) for 24-72 h increased DNA synthesis by 1.5- to 3-fold; PDGF-BB was more potent than PDGF-AA. Although PDGF increased cell replication in all cell zones, the effects of both PDGF-AA and -BB were preferentially greater in the periosteal fibroblast zone, in which, at 3.3 nM, the labeling index (LI) was increased by 3-fold with AA and by 5-fold with BB. Cell replication of the bone surface cell (osteoblast) layer was increased by 2-fold with AA and by 2.5-fold with BB, whereas replication in the intermediate osteoprogenitor zone increased by 50% with AA and by 2.5-fold with BB. The increase in cell replication was associated with a significant inhibition of bone matrix-forming surfaces, with PDGF-BB being more potent at equivalent doses than -AA after 24-72 h of continuous treatment. Continuous or intermittent exposure to PDGF-AA or PDGF-BB for 24-72 h stimulated neither the rate of collagen synthesis nor organized bone matrix formation in rat calvariae. In addition, PDGF-BB at 0.03-3.3 nM increased the number of osteoclasts and the percent eroded surface by 2- to 3-fold. Our studies show that PDGF-AA and -BB are mitogens affecting multiple bone cells, including those of the osteoblast and osteoclast lineage. Treatment with PDGF severely disrupted and inhibited bone matrix formation, and there was no evidence to show that cells incorporating [3H]thymidine differentiated into mature osteoblasts within the time frame of these experiments. In fetal rat calvaria, the most significant consequence of treatment with PDGF was the selective stimulation of fibroblast replication and function.
authors.affiliation: Skeletal Diseases Research Group, Lilly Research Laboratories, Indianapolis, Indiana 46283.
authors.forename: J M
authors.initials: JM
authors.lastname: Hock
authors.forename: E
authors.initials: E
authors.lastname: Canalis
mesh_terms: D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D001857:Bone Matrix / Q000187:drug effects; D001862:Bone Resorption / Q000139:chemically induced; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D004247:DNA / Q000096:biosynthesis; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D010006:Osteoblasts / Q000187:drug effects* / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D051381:Rats
chemical_list: D010982:Platelet-Derived Growth Factor; D003094:Collagen; D004247:DNA