Cellular mechanism of decreased bone in Brtl mouse model of OI: imbalance of decreased osteoblast function and increased osteoclasts and their precursors.
The Brtl mouse, a knock-in model for moderately severe osteogenesis imperfecta (OI), has a G349C substitution in half of type I collagen alpha1(I) chains. We studied the cellular contribution to Brtl bone properties. Brtl cortical and trabecular bone are reduced before and after puberty, with BV/TV decreased 40-45%. Brtl ObS/BS is comparable to wildtype, and Brtl and wildtype marrow generate equivalent number of colony-forming units (CFUs) at both ages. However, OcS/BS is increased in Brtl at both ages (36-45%), as are TRACP(+) cell numbers (57-47%). After puberty, Brtl ObS/BS decreases comparably to wildtype mice, but osteoblast matrix production (MAR) decreases to one half of wildtype values. In contrast, Brtl OcS falls only moderately (approximately 16%), and Brtl TRACP staining remains significantly elevated compared with wildtype. Consequently, Brtl BFR decreases from normal at 2 mo to one half of wildtype values at 6 mo. Immunohistochemistry and real-time RT-PCR show increased RANK, RANKL, and osteoprotegerin (OPG) levels in Brtl, although a normal RANKL/OPG ratio is maintained. TRACP(+) precursors are markedly elevated in Brtl marrow cultures and form more osteoclasts, suggesting that osteoclast increases arise from more RANK-expressing precursors. We conclude that osteoblasts and osteoclasts are unsynchronized in Brtl bone. This cellular imbalance results in declining BFR as Brtl ages, consistent with reduced femoral geometry. The disparity in cellular number and function results from poorly functioning osteoblasts in addition to increased RANK-expressing precursors that respond to normal RANKL/OPG ratios to generate more bone-resorbing osteoclasts. Interruption of the stimulus that increases osteoclast precursors may lead to novel OI therapies.
Uveges
Thomas E
TE
Bone and Extracellular Matrix Branch, NICHD, NIH, Bethesda, Maryland 20892, USA.
Collin-Osdoby
Patricia
P
Cabral
Wayne A
WA
Ledgard
Felicia
F
Goldberg
Leah
L
Bergwitz
Clemens
C
Forlino
Antonella
A
Osdoby
Philip
P
Gronowicz
Gloria A
GA
Marini
Joan C
JC
D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D001842:Bone and Bones / Q000378:metabolism*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism*; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D053245:RANK Ligand / Q000378:metabolism; D013234:Stem Cells
D000596:Amino Acids; D053245:RANK Ligand; C015484:pyridinoline