Peak bone mass is a major determinant of osteoporosis. The bone mineral acquired during childhood and adolescence is critical to attaining maximal peak bone mass. During the critical two year pubertal window surrounding peak bone accrual about 26% of final adult bone mass is acquired;children whom are physically active are known to accrue 10-40% more bone (region specific) than inactive children. Bone is inherently mechanosensitive, responding and adapting to its mechanical environment. Bone formation occurs in response to high mechanical loads;often changing geometry to strengthen the skeleton. The largest physiological loads bones typically experience are from muscles, and bone strength is proportional to muscle mass. Osteogenesis imperfecta (OI) is a heritable connective tissue disorder characterized by small stature, reduced bone mineral density and frequent fractures. OI patients reportedly have muscle weakness. In a single study OI children were found to have reduced muscle strength and decreased exercise tolerance relative to healthy age-matched children. It is unclear though, if the reduced muscle strength and exercise tolerance are a consequence of sedentary lifestyles or inherent to the pathology of OI. Preliminary studies of oim mice (osteogenesis imperfecta model) suggest that the reduced muscle mass in oim/oim mice is a reflection of their reduced size and physical activity, and that the relative contractile generating capacity [peak tetanic tension (Po)/g of muscle] is not significantly different from age-matched wildtype mice. Exercise and physical activity during childhood and adolescence are essential for an individual to attain their full peak bone mass potential;the lack of physical activity in OI children particularly during this critical window of maximal bone accrual is setting OI patients up for even poorer bone health as adults. We propose to utilize two mouse models of osteogenesis imperfecta: the oim mouse which models mild and severe OI due to haploinsufficiency [oim/+ (models human type I OI) and oim/oim (human OI type III)] and the new G610C COL1A2 mouse which models dominant negative molecular mechanisms [G610C/+ (models human type I and IV OI)] to investigate the impact of non-weight bearing (swimming) and weight bearing (treadmill) exercise on muscle strength and bone quality and strength. Specifically, in Aim 1 we will evaluate activity and selected muscles in 6 week old (adolescence-baseline and age of initiation of treatment) and 4 month old (age of peak bone mass) mice to determine if oim and/or G610C mice have an inherent muscle weakness or pathology (reduced muscle mass, fiber cross-sectional area and/or contractile generating capacity) that may contribute to bone weakness and whether physical activity is altered relative to wildtype littermates.
In Aim 2, we will evaluate femoral geometry (uCT) and biomechanics (torsional loading to failure) of 6 week and 4 month old oim and G610C mice in relation to mineral and matrix, physicochemical and mechanical properties of the bone by multi-scale analyses ( FTIR, Raman and scanning acoustic microscopy) to determine the structure/chemistry/biomechanical relationship at the multi-scale level.
In Aim 3 we will determine if swimming (non-weight bearing) and/or running on a treadmill (weight bearing) exercise regimens will increase muscle contractile generating capacity and endurance, alter the molecular structure of bone mineral and matrix, and improve bone physicochemical properties/biomechanical integrity in oim and G610C mouse bones.

Public Health Relevance

Osteogenesis imperfecta is a heritable connective tissue disorder characterized by muscle weakness and skeletal fragility. We will evaluate the potential therapeutic effects of increasing muscle strength and endurance, and concomitantly bone quality and strength by weight-bearing and non-weight bearing exercise regimens using two distinct osteogenesis imperfecta mouse models.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR055907-03
Application #
8277100
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Sharrock, William J
Project Start
2010-06-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$323,853
Indirect Cost
$107,853
Name
University of Missouri-Columbia
Department
Biochemistry
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Yao, Xiaomei; Carleton, Stephanie M; Kettle, Arin D et al. (2013) Gender-dependence of bone structure and properties in adult osteogenesis imperfecta murine model. Ann Biomed Eng 41:1139-49
Gentry, Bettina A; Ferreira, J Andries; McCambridge, Amanda J et al. (2010) Skeletal muscle weakness in osteogenesis imperfecta mice. Matrix Biol 29:638-44