Mapping quantitative trait loci that influence blood levels of alkaline
phosphatase in MRL/MpJ and SJL/J mice
A.K. Srivastava
a,b,
*
, G. Masinde
a,b
,H.Yu
a
, D.J. Baylink
a,b,c
, S. Mohan
a,b,c
a
Musculoskeletal Disease Center, JLP VA Medical Center, Loma Linda, CA, 92357, United States
b
Department of Medicine, Loma Linda University, Loma Linda, CA 92354, United States
c
Department of Biochemistry, Loma Linda University, Loma Linda, CA 92354, United States
Received 6 April 2004; revised 12 July 2004; accepted 21 July 2004
Available online 22 September 2004
Abstract
To examine the hypothesis that serum alkaline phosphatase (ALP) levels have a heritable component, we analyzed blood from two
inbred strains of mice, MRL/MpJ and SJL, which exhibit 90% difference in total serum ALP activity (268 F 26 vs. 140 F 15 U/l,
respectively, P b 0.001). A genome-wide scan was carried out using 137 polymorphic markers in 518 F2 female mice. Serum ALP
activity in the F2 progeny showed a normal distribution with an estimated heritability of 56%. Genome-wide scan for cosegregation of
genetic marker data with serum ALP activity revealed three major quantitative trait loci (QTL), one each on chromosomes 2 (LOD score
3.8), chromosome 6 (LOD score 12.0), and chromosome 14 (LOD score 3.7). In addition, there was one suggestive QTL on
chromosome 2 (LOD score of 3.3). In aggregate, these QTLs explain 22.5% of variance in serum ALP between these two strains.
Serum ALP showed a moderate but significant correlation with body weight adjusted total body bone mineral density (r = 0.12, P =
0.0108) and periosteal circumference at midshaft tibia (r = 0.15, P = 0.0006) in F2 mice. The chromosome 6 locus harboring the major
serum ALP QTL also contains a major BMD and bone size QTL, identified earlier, between these two strains of mice; in addition, this
QTL is also close to the locus that regulates IGF-I levels (LOD score 8-9) in C3HB6 F2 mice. These common QTLs indicate that the
observed difference in ALP and BMD or bone size may be regulated by same loci (or genes). Accordingly, the osteoblast cells isolated
from femur and tibia of MRL mice showed a significantly higher number of ALP +ve cells/colony and two- to threefold higher ALP
activity ( P b 0.001) as compared to the cells isolated from SJL mice, thus suggesting that differences in serum ALP between MRL and
SJL reflect difference in ALP expression from osteoblasts from these strains of mice. These data suggest that serum ALP levels are
genetically determined and correlate with cellular mechanisms that differentiate BMD accrual in these two strains of mice. The findings
that ALP and BMD traits share the same loci on chromosome 6 suggest a role for genetic determinants of bone formation in overall BMD
accretion.
D 2004 Elsevier Inc. All rights reserved.
Keywords: Alkaline phosphatase; Quantitative trait loci (QTL); Bone formation markers; Bone mineral density; Bone size
Introduction
It is well established that genetic factors explain a
substantial proportion of the variation in peak bone density
[1–3]. The peak bone mass is the net result of the overall
balance between the rate of bone formation (bone gain) and
the rate of bone resorption (bone loss). The genetic effects on
bone mass are presumably mediated through genes affecting
the rate of bone formation as well as the rate of bone
resorption. Therefore, identification of the gene(s) involved
in bone turnover or remodeling will provide important insight
into how the genetic makeup of some individuals increases
their susceptibility to osteoporosis. This hypothesis has
guided a few studies that reported a significant heritable
component to variation in bone turnover markers [4,5].
Bone turnover can be assessed from a number of
biochemical markers in blood, of which type-I procollagen
8756-3282/$ - see front matter D 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.bone.2004.07.011
* Corresponding author. Musculoskeletal Disease Center (151), Loma
Linda VA Healthcare Systems, 11201 Benton Street, Loma Linda, CA
92357. Fax: +1 909 796 1680.
E-mail address: apurva.srivastava@med.va.gov (A.K. Srivastava).
Bone 35 (2004) 1086 – 1094
www.elsevier.com/locate/bone