Regulation of osteocalcin production and bone resorption by 1,25-dihydroxyvitamin D3 in mouse long bones: interaction with the bone-derived growth factors TGF-beta and IGF-I.
Bone cells produce multiple growth factors that have effects on bone metabolism and can be incorporated into the bone matrix. Interplay between these bone-derived growth factors and calciotropic hormones has been demonstrated in cultured bone cells. The present study was designed to extend these observations by examining the interactions between either transforming growth factor-beta (TGF-beta) or insulin-like growth factor-I (IGF-I) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in a mouse long bone culture model with respect to osteocalcin production and bone resorption. In contrast to the stimulation in rat and human, in the fetal mouse long bone cultures, 1,25(OH)2D3 caused a dose-dependent inhibition of osteocalcin production. Both the osteocalcin content in the culture medium and in the extracts of the long bones was reduced by 1,25(OH)2D3. This effect was not specific for fetal bone because 1,25(OH)2D3 also reduced osteocalcin production by the neonatal mouse osteoblast cell line MC3T3. TGF-beta inhibited whereas IGF-I dose-dependently increased osteocalcin production in mouse long bones. The combination of TGF-beta and 1,25(OH)2D3 did not result in a significantly different effect compared with each of these compounds alone. The IGF-I effect was completely blocked by 1,25(OH)2D3. In the same long bones as used for the osteocalcin measurements, we performed bone resorption analyses. Opposite to its effect on osteocalcin, 1,25(OH)2D3 dose-dependently stimulated bone resorption. TGF-beta reduced and IGF-I did not change basal (i.e., in the absence of hormones) bone resorption. Our results show that 1,25(OH)2D3-enhanced bone resorption is dose-dependently inhibited by TGF-beta and IGF-I. Regression analysis demonstrated a significant negative correlation between 1,25(OH)2D3-induced bone resorption and osteocalcin production. The specificity for their effect on 1,25(OH)2D3-stimulated bone resorption was assessed by testing the effects of TGF-beta and IGF-I in combination with parathyroid hormone (PTH). Like 1,25(OH)2D3, PTH dose-dependently stimulates bone resorption. However, PTH-stimulated bone resorption was not affected by TGF-beta. Like 1,25(OH)2D3-stimulated bone resorption, IGF-I inhibited the PTH effect but at a 10-fold higher concentration compared with 1,25(OH)2D3. In conclusion, the present study demonstrates growth factor-specific interactions with 1,25(OH)2D3 in the control of osteocalcin production and bone. With respect to bone resorption, these interactions are also hormone specific. The present data thereby support and extend the previous observations that interactions between 1,25(OH)2D3 and bone-derived growth factors play an important role in the control of bone metabolism. These data together with the fact that TGF-beta and IGF-I are present in the bone matrix and potentially can be released during bone resorption support the concept that growth factors may control the effects of calciotropic hormones in bone in a localized and possibly temporal manner. Finally, in contrast to human and rat, in mice 1,25(OH)2D3 reduces osteocalcin production and this reduction is paralleled by stimulation of bone resorption by 1,25(OH)2D3. These data thereby show a dissociation between osteocalcin production and bone resorption.
Staal
A
A
Department of Internal Medicine III, Erasmus University Medical School, Rotterdam, The Netherlands.
Geertsma-Kleinekoort
W M
WM
Van Den Bemd
G J
GJ
Buurman
C J
CJ
Birkenhäger
J C
JC
Pols
H A
HA
Van Leeuwen
J P
JP
D000818:Animals; D000831:Animals, Newborn; D001862:Bone Resorption / Q000378:metabolism*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D002117:Calcitriol / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D003470:Culture Media / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005333:Fetus; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051379:Mice; D015675:Osteocalcin / Q000096:biosynthesis* / Q000378:metabolism; D010281:Parathyroid Hormone / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D003470:Culture Media; D010281:Parathyroid Hormone; D016212:Transforming Growth Factor beta; D015675:Osteocalcin; D007334:Insulin-Like Growth Factor I; D002117:Calcitriol