title: Parathyroid hormone-related protein modulates the effect of transforming growth factor-beta on deoxyribonucleic acid and collagen synthesis in fetal rat bone cells.
abstract: Proteins with biochemical function and sequence similarity to PTH are produced by many tumors associated with hypercalcemia and may have a role in pathological bone remodeling. Synthetic polypeptides comprising the amino-terminus of human PTH-related protein (PTH-rp) were examined for effects in intact fetal rat calvariae, and in osteoblast-enriched (ob) cultures isolated from fetal rat parietal bone. In cultured calvariae, 0.5-5 nM PTH-rp stimulated [3H]thymidine incorporation into DNA by 25-70% after 24 h of treatment and decreased relative [3H]proline incorporation into collagen by 50%; the inhibitory effect on collagen production was not altered by hydroxyurea, which decreased DNA synthesis by 85%. PTH-rp also increased [3H]hydroxyproline levels by 100% in culture medium from bones prelabeled with [3H]proline, indicating accelerated matrix turnover. In contrast to results in intact calvariae, PTH-rp had little effect on basal DNA and collagen synthesis in serum-deprived ob cultures. However, when ob cultures were treated with transforming growth factor type beta at concentrations similar to those found in calvarial culture medium, 0.02-2 nM PTH-rp enhanced DNA synthesis and decreased collagen production. Furthermore, equimolar PTH-rp and PTH concentrations similarly displaced 125I-PTH-rp binding and enhanced cAMP synthesis in ob cultures. These studies suggest that PTH-rp regulates osteoblastic cell activity primarily through PTH-related pathways and may act in part by modulating the effects of locally produced transforming growth factor-beta in bone.
authors.affiliation: Department of Medicine (Endocrine Section), Saint Francis Hospital and Medical Center, Hartford, Connecticut 06105.
authors.forename: M
authors.initials: M
authors.lastname: Centrella
authors.forename: E
authors.initials: E
authors.lastname: Canalis
authors.forename: T L
authors.initials: TL
authors.lastname: McCarthy
authors.forename: A F
authors.initials: AF
authors.lastname: Stewart
authors.forename: J J
authors.initials: JJ
authors.lastname: Orloff
authors.forename: K L
authors.initials: KL
authors.lastname: Insogna
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D004247:DNA / Q000096:biosynthesis*; D005333:Fetus / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism / Q000494:pharmacology*; D009924:Organ Culture Techniques; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D051381:Rats; D011919:Rats, Inbred Strains; D015291:Transforming Growth Factors / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D009363:Neoplasm Proteins; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D015291:Transforming Growth Factors; D003094:Collagen; D004247:DNA