Genetic regulation of bone strength: a review of animal model studies

Abstract

Population-and family-based studies have established that fragility fracture risk is heritable; yet, the genome-wide association studies published to date have only accounted for a small fraction of the known variation for fracture risk of either the femur or the lumbar spine. Much work has been carried out using animal models toward finding genetic loci that are associated with bone strength. Studies using animal models overcome some of the issues associated with using patient data, but caution is needed when interpreting the results. In this review, we examine the types of tests that have been used for forward genetics mapping in animal models to identify loci and/or genes that regulate bone strength and discuss the limitations of these test methods. In addition, we present a summary of the quantitative trait loci that have been mapped for bone strength in mice, rats and chickens. The majority of these loci co-map with loci for bone size and/or geometry and thus likely dictate strength via modulating bone size. Differences in bone matrix composition have been demonstrated when comparing inbred strains of mice, and these matrix differences may be associated with differences in bone strength. However, additional work is needed to identify loci that act on bone strength at the materials level.

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“…Lastly, variation in body size and cross‐sectional properties can reflect genetic differences between populations. Some proportion of bone cross‐sectional properties and bone length is heritable, though the extent of genetic control remains poorly understood (Adams & Ackert‐Bicknell, 2015; Duren, Seselj, Froehle, Nahhas, & Sherwood, 2013; Holliday, 1997; Peacock et al, 2005; Roseman & Auerbach, 2015; Ruff, Holt, & Trinkaus, 2006). Joint surfaces and bone length “grow ahead” of body mass, suggesting growth towards genetically canalized endpoint, which may vary between populations being compared (Frisancho, Guire, Babler, Borken, & Way, 1980; Roseman & Auerbach, 2015; Ruff, 2007; Ruff et al, 2013; Saunders, 2008).…”

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“…As has been stated herein previously, BMD is correlated to strength, but it is not a perfect predictor of strength (Figure 2). Skeletal strength is achieved via integration of the mass, architectural distribution, and compositional quality of its constituent matrix material (72). Although deficiency in any of these contributors to maintaining integrity reduces bone strength, genetic mapping has foremost associated skeletal strength with bone mass and morphology.…”

“…The simplest choice has been used most widely, subjecting long bone diaphyseal cortex to flexural loading (i.e., bending). Together with measurement of cross-sectional (transverse) geometry of each specimen via volumetric imaging, such as provided by X-ray microtomography, estimates of the tissue- or material-level mechanical integrity can be calculated (72, 74). Without these geometrical measurements, the structural tests often reflect bone size and shape, as borne out in mapping studies that reveal coincident QTL for whole bone strength and measures of bone size (72).…”

“…In mice, genetic mapping studies that include direct measures of bone strength have identified approximately 50 QTL, but in many instances such attributions to strength were merely reflecting bone size and the geometrical indices that dictate structural resistance to bending (reviewed in (72)). A prime example of this is the locus mapped to Chr 4 and centered at ~60 cM, demonstrating a high degree of coincidence between the geometrical predictions and direct measures of whole bone structural performance.…”

“…In rats, approximately 41 discrete loci have been identified for phenotypes measuring whole bone strength and/or geometry (reviewed in (72)), with 23 loci mapping only to phenotypes describing geometry and/or size and 7 co-mapping strength and geometry phenotypes. The remaining 11 loci, which do not report co-mapping of a geometry phenotype, may include loci that regulate matrix-level quality but none had sufficient resolution to reduce identified QTLs to gene level.…”