Cellular Mechanism of Decreased Bone in Brtl Mouse Model of OI: Imbalance of Decreased Osteoblast Function and Increased Osteoclasts and Their Precursors

• Published in: Journal of bone and mineral research Vol. 23; no. 12; pp. 1983 - 1994
• Main Authors: Uveges, Thomas E, Collin‐Osdoby, Patricia, Cabral, Wayne A, Ledgard, Felicia, Goldberg, Leah, Bergwitz, Clemens, Forlino, Antonella, Osdoby, Philip, Gronowicz, Gloria A, Marini, Joan C
• Format: Journal Article
• Language: English
• Published: Washington, DC John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR) 01-12-2008; Amer Soc Bone & Mineral Res
• Subjects: Amino Acids - chemistry; Animals; Bone and Bones - metabolism; Bone Marrow Cells - cytology; Brtl mouse; Disease Models, Animal; Fibroblasts - metabolism; histomorphometry; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Original; Osteoblasts - metabolism; osteoclast; Osteoclasts - metabolism; Osteogenesis Imperfecta - genetics; RANK Ligand - metabolism; RANKL/osteoprotegerin; Stem Cells; type I collagen
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1359/jbmr.080804

The Brtl mouse, a knock‐in model for moderately severe osteogenesis imperfecta (OI), has a G349C substitution in half of type I collagen α1(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 (∼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.