title: Tibial loading increases osteogenic gene expression and cortical bone volume in mature and middle-aged mice.
abstract: There are conflicting data on whether age reduces the response of the skeleton to mechanical stimuli. We examined this question in female BALB/c mice of different ages, ranging from young to middle-aged (2, 4, 7, 12 months). We first assessed markers of bone turnover in control (non-loaded) mice. Serum osteocalcin and CTX declined significantly from 2 to 4 months (p<0.001). There were similar age-related declines in tibial mRNA expression of osteoblast- and osteoclast-related genes, most notably in late osteoblast/matrix genes. For example, Col1a1 expression declined 90% from 2 to 7 months (p<0.001). We then assessed tibial responses to mechanical loading using age-specific forces to produce similar peak strains (-1300 µε endocortical; -2350 µε periosteal). Axial tibial compression was applied to the right leg for 60 cycles/day on alternate days for 1 or 6 weeks. qPCR after 1 week revealed no effect of loading in young (2-month) mice, but significant increases in osteoblast/matrix genes in older mice. For example, in 12-month old mice Col1a1 was increased 6-fold in loaded tibias vs. controls (p = 0.001). In vivo microCT after 6 weeks revealed that loaded tibias in each age group had greater cortical bone volume (BV) than contralateral control tibias (p<0.05), due to relative periosteal expansion. The loading-induced increase in cortical BV was greatest in 4-month old mice (+13%; p<0.05 vs. other ages). In summary, non-loaded female BALB/c mice exhibit an age-related decline in measures related to bone formation. Yet when subjected to tibial compression, mice from 2-12 months have an increase in cortical bone volume. Older mice respond with an upregulation of osteoblast/matrix genes, which increase to levels comparable to young mice. We conclude that mechanical loading of the tibia is anabolic for cortical bone in young and middle-aged female BALB/c mice.
authors.affiliation: Department of Orthopaedic Surgery, Washington University, St Louis, Missouri, United States of America. silvam@wustl.edu
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Silva
authors.forename: Michael D
authors.initials: MD
authors.lastname: Brodt
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Lynch
authors.forename: Abby L
authors.initials: AL
authors.lastname: Stephens
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wood
authors.forename: Roberto
authors.initials: R
authors.lastname: Civitelli
mesh_terms: D000367:Age Factors; D000818:Animals; D024042:Collagen Type I / Q000097:blood / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D015675:Osteocalcin / Q000097:blood; D010012:Osteogenesis / Q000502:physiology; D010455:Peptides / Q000097:blood; D013314:Stress, Mechanical; D013977:Tibia / Q000166:cytology / Q000378:metabolism* / Q000502:physiology*
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D010455:Peptides; C052929:collagen type I trimeric cross-linked peptide; D015675:Osteocalcin