title: Platelet derived growth factor stimulates chondrocyte proliferation but prevents endochondral maturation.
abstract: Platelet-derived growth factor (PDGF) is a cytokine released by platelets at sites of injury to promote mesenchymal cell proliferation. Since many bone wounds heal by endochondral bone formation, we examined the response of chondrocytes in the endochondral lineage to PDGF. Confluent cultures of rat costochondral resting zone cartilage cells were incubated with 0-300 ng/mL PDGF-BB for 24 h to determine whether dose-dependent changes in cell proliferation (cell number and [3H]-thymidine incorporation), alkaline phosphatase specific activity, [35S]-sulfate incorporation, or [3H]-proline incorporation into collagenase-digestible protein (CDP) or noncollagenase-digestible protein (NCP), could be observed. Long-term effects of PDGF were assessed in confluent cultures treated for 1, 2, 4, 6, 8, or 10 d with 37.5 or 150 ng/mL PDGF-BB. To determine whether PDGF-BB could induce resting zone chondrocytes to change maturation state to a growth zone chondrocyte phenotype, confluent resting zone cell cultures were treated for 1, 2, 3, or 5 d with 37.5 or 150 ng/ml PDGF-BB and then challenged for an additional 24 h with 1,25-(OH)2D3. PDGF-BB caused a dose-dependent increase in cell number and [3H]-thymidine incorporation at 24 h. The proliferative effect of the cytokine decreased with time. PDGF-BB had no effect on alkaline phosphatase at 24 h, but at later times, the cytokine prevented the normal increase in enzyme activity seen in post-confluent cultures. This effect was primarily on the cells and not on the matrix. PDGF-BB stimulated [35S]-sulfate incorporation at all times examined, but had no effect on [3H]-proline incorporation into either the CDP or NCP pools. Thus, percent collagen production was not changed. Treatment of the cells for up to 5 d with PDGF-BB failed to elicit a 1,25-(OH)2D3 responsive phenotype typical of rat costochondral growth zone cartilage cells. These results show that committed chondrocytes can respond to PDGF-BB with increased proliferation. The effect of the cytokine is to enhance cartilage matrix production, but at the same time to prevent progression of the cells along the endochondral maturation pathway.
authors.affiliation: OsteoBiologics, Inc., San Antonio, TX, USA.
authors.forename: K
authors.initials: K
authors.lastname: Kieswetter
authors.forename: Z
authors.initials: Z
authors.lastname: Schwartz
authors.forename: M
authors.initials: M
authors.lastname: Alderete
authors.forename: D D
authors.initials: DD
authors.lastname: Dean
authors.forename: B D
authors.initials: BD
authors.lastname: Boyan
mesh_terms: D000469:Alkaline Phosphatase / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000077214:Becaplermin; D001861:Bone Regeneration / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D003094:Collagen / Q000096:biosynthesis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D006801:Humans; D007399:Interphase / Q000187:drug effects / Q000502:physiology; D008297:Male; D009994:Osmolar Concentration; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011392:Proline / Q000032:analysis / Q000378:metabolism; D014176:Protein Biosynthesis; D011506:Proteins / Q000187:drug effects; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D013431:Sulfates / Q000032:analysis / Q000378:metabolism; D013462:Sulfur Radioisotopes; D013936:Thymidine / Q000032:analysis / Q000378:metabolism; D013997:Time Factors; D014316:Tritium
chemical_list: D010982:Platelet-Derived Growth Factor; D011506:Proteins; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; D013431:Sulfates; D013462:Sulfur Radioisotopes; D014316:Tritium; D000077214:Becaplermin; D003094:Collagen; D011392:Proline; D000469:Alkaline Phosphatase; D013936:Thymidine