Mechanisms underlying catabolic and anabolic functions of parathyroid hormone on bone by combination of culture systems of mouse cells.
Since bone resorption and formation by continuous and intermittent parathyroid hormone (PTH) treatments involve various types of cells in bone, this study examined the underlying mechanism by combining culture systems using mouse primary calvarial osteoblasts and bone marrow cells. The PTH/PTHrP receptor (PTH1R) expression and the cAMP accumulation in response to PTH were increased in accordance with the differentiation of osteoblasts. Osteoclast formation was strongly induced by continuous PTH treatment in the monolayer co-culture of osteoblasts and bone marrow cells, which was associated with RANKL expression in differentiated osteoblasts. Bone formation determined by ALP activity and the type I collagen mRNA expression was stimulated by intermittent PTH treatment in the monolayer co-culture and in the bone marrow cell layer of the separated co-culture in a double chamber dish, but not in the culture of bone marrow cells alone. The stimulation in the separated co-culture, accompanied by IGF-I production by osteoblasts, was abolished when bone marrow cells were derived from knockout mice of insulin-receptor substrate-1 (IRS-1-/-) or when osteoblasts were from PTH1R-/- mice. We conclude that differentiated osteoblasts are most likely the direct target of both continuous and intermittent PTH, while bone marrow cells are likely the effector cells. The osteoblasts stimulated by continuous PTH express RANKL which causes osteoclastogenesis from the precursors in bone marrow via cell-to-cell contact, leading to bone resorption; while the osteoblasts stimulated by intermittent PTH secrete IGF-I which activates IRS-1 in osteoblast precursors in bone marrow via a paracrine mechanism, leading to bone formation.
Shinoda
Yusuke
Y
Department of Sensory & Motor System Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Kawaguchi
Hiroshi
H
Higashikawa
Akiro
A
Hirata
Makoto
M
Miura
Toshiki
T
Saito
Taku
T
Nakamura
Kozo
K
Chung
Ung-il
UI
Ogata
Naoshi
N
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D001842:Bone and Bones / Q000378:metabolism*; D002450:Cell Communication; D018920:Coculture Techniques; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I; D051379:Mice; D010006:Osteoblasts / Q000166:cytology; D010012:Osteogenesis; D010281:Parathyroid Hormone / Q000502:physiology*; D053245:RANK Ligand / Q000096:biosynthesis
D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010281:Parathyroid Hormone; D053245:RANK Ligand; D007334:Insulin-Like Growth Factor I