Submitted on March 27, 2008
Revised on August 4, 2008
Accepted on August 5, 2008
Complex genetic regulation of bone mineral density and insulin-like growth factor-I in C57BL/6J-Chr #A/J/NaJ chromosome substitution strains
Kristen E Govoni1, Leah Rae Donahue2, Coleen Marden2, and Subburaman Mohan3*
1 Jerry L. Pettis VA Medical Center
2 The Jackson Laboratory
3 Jerry L. Pettis Memorial VA Medical Center
* To whom correspondence should be addressed. E-mail: Subburaman.Mohan{at}va.gov.
Low bone mineral density (BMD) is a phenotype associated with osteoporosis and increased risk of fracture. Since 60 to 80% of variation in BMD is associated with genetic factors, we used the novel approach of chromosome substitution strains (CSS) to identify chromosomes that harbor genes that regulate BMD. Specifically, we evaluated 24 week old C57BL/6J-Chr #A/J/NaJ CSS (n = 7 to 18) in which each chromosome in the host C57BL/6J strain is replaced by a corresponding chromosome from the donor A/J strain (19 autosomes, X, Y). We determined several A/J chromosomes contribute to body weight (BW), percent body fat (BF), whole body areal BMD (aBMD), and serum insulin-like growth factor (IGF)-I in both a positive and negative manner when compared with C57BL/6J. Specifically, C57BL/6J-Chr 5A/J/NaJ (B.A-5) (males) and B.A-1 and 2 (females) contributed to increased BW, whereas B.A- 3, 4, 8, 9, 12, and 18 (males) and B.A-3, and 4 (females) contributed to reduced BW. B.A- 5 (males) and B.A-1 and 13 (females) contributed to increased BF. B.A- 4 and 12 (males) and B.A-3 and 4 (females) contributed to increased aBMD and B.A-5 (males) and 13 (females) contributed to reduced aBMD independent of BW. To determine if similar chromosomes regulate aBMD and IGF-I, we determined serum concentrations of IGF-I. B.A-14 (males) and B.A-4 to 7, 12 to 15, 17, 19, and Y (females) contributed to increased IGF-I and male B.A-3 contributed to reduced IGF-I. Overall, we identified several gender-dependent and -independent loci that regulate aBMD and IGF-I in adult mice.
