Abstract
Inbred strain-specific differences in mice exist in bone cross-sectional geometry, mechanical properties, and indices of bone formation. Inbred strain-specific responses to external stimuli also exist, but the role of background strain in response to genetic deletion is not fully understood. Biglycan (bgn) deficiency impacts bone through negative regulation of osteoblasts, resulting in extracellular matrix alterations and decreased mechanical properties. Because osteoblasts from C3H/He (C3H) mice are inherently more active versus osteoblasts from other inbred strains, and the bones of C3H mice are less responsive to other insults, it was hypothesized that C3H mice would be relatively more resistant to changes associated with bgn deficiency compared with C57BL6/129 (B6;129) mice. Changes in mRNA expression, tissue composition, mineral density, bone formation rate, cross-sectional geometry, and mechanical properties were studied at 8 and 11 wk of age in the tibias of male wildtype and bgn-deficient mice bred on B6;129 and C3H background strains. Bgn deficiency altered collagen cross-linking and gene expression and the amount and composition of mineral in vivo. In bgn's absence, changes in collagen were independent of mouse strain. Bgn-deficiency increased the amount of mineral in both strains, but changes in mineral composition, cross-sectional geometry, and mechanical properties were dependent on genetic background. Bgn deficiency influenced the amount and composition of bone in mice from both strains at 8 wk, but C3H mice were better able to maintain properties close to wildtype (WT) levels. By 11 wk, most properties from C3H knockout (KO) bones were equal to or greater than WT levels, whereas phenotypic differences persisted in B6;129 KO mice. This is the first study into mouse strain-specific changes in a small leucine-rich proteoglycan gene disruption model in properties across the bone hierarchy and is also one of the first to relate these changes to mechanical competence. This study supports the importance of genetic factors in determining the response to a gene deletion and defines biglycan's importance to collagen and mineral composition in vivo.
Highlights
MICE WITH TARGETED mutations in bone matrix proteins have been used to study the proteins’ roles in regulating bone matrix deposition, composition, and mechanical integrity and aid in understanding how these functions relate to bone disease and fracture etiology.[1]. One such model of disrupted protein production is the biglycan-deficient mouse.[2,3,4] Bgn is a small leucinerich proteoglycan (SLRP) that is enriched in the extracellular matrix (ECM) of bone and other connective tissues.[5,6,7] Bgn-deficient mice exhibit a defect in the growth and differentiation of osteoblasts resulting in decreased bone production and function.[8,9,10] Eleven-week-old bgndeficient male mice exhibited decreased tissue-level yield strength, a property that is independent of the amount of tissue present.[11]. Decreased tissue-level strength
The hybrid C57BL6/129 (B6;129) strain has been used as the background strain for many genetic knockouts (KO), including bgn deficiency.[2,11] In the tibias of male mice at 3 mo of age, volumetric BMD (vBMD) is similar in B6(28) and B6;129 mice,(11) suggesting that the B6;129 mouse is an appropriate low bone mass strain to use in comparison with the high bone mass C3H mouse
Because the bgn-deficient phenotype is strongest in the male tibia,(11) changes mRNA expression, tissue composition (Raman microspectroscopy), bone formation, cross-sectional geometry and vBMD, and mechanical properties were studied in the tibias of 8- and 11-wk-old male WT and bgn-deficient mice bred on B6;129 and C3H backgrounds to uncover inbred strain-specific responses to bgn deficiency across multiple levels of the bone hierarchy and to link phenotypic changes to functional competence
Summary
MICE WITH TARGETED mutations in bone matrix proteins have been used to study the proteins’ roles in regulating bone matrix deposition, composition, and mechanical integrity and aid in understanding how these functions relate to bone disease and fracture etiology.[1]. Biglycan (and bgn deficiency) is known to impact bone growth and bone mass in mice When this genetic deletion is superimposed onto genetic backgrounds encoding for high and low bone mass/density, the resulting skeletal effects could greatly differ. Because the bgn-deficient phenotype is strongest in the male tibia,(11) changes mRNA expression (qRT-PCR), tissue composition (Raman microspectroscopy), bone formation (dynamic histomorphometry), cross-sectional geometry and vBMD (mCT), and mechanical properties (four-point bending) were studied in the tibias of 8- and 11-wk-old male WT and bgn-deficient mice bred on B6;129 and C3H backgrounds to uncover inbred strain-specific responses to bgn deficiency across multiple levels of the bone hierarchy and to link phenotypic changes to functional competence
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