Identification of Genes That Modulate Bone Loss During Mechanical Unloading

Bone is a dynamic tissue that senses and responds to mechanical cues. On these lines, the tissue also recognizes and responds to absence of such signals. While mechanical stimuli is met with bone anabolic responses, loss/lack of mechanical input or unloading is detrimental to bone and is accompanied by elevated bone catabolic and suppressed bone anabolic activity. For this very reason, patients confined to bed rest (paraplegic, quadriplegic, stroke, spinal cord injury), astronauts in space, and individuals who do not dynamically load their bones experience bone loss. This bone loss however, varies significantly between individuals. This unloading induced loss is variable even in astronaut cohorts where other extraneous factors including diet and exercise are strictly regulated, suggesting genetics as the key modulator of this skeletal response.

The objective of this dissertation was therefore to identify the genes that modulate skeletal response to mechanical unloading, and also to test the extent of genetic differences necessary to elicit a differential response to unloading. The aims of the dissertation were, 1. To identify genetic candidates that can modulate bone response to unloading, using previously generated genomic data from a genetic linkage study, and then validation of these genes by hindlimb unloading; 2. To determine if even minor genetic variations in the form of a few allelic differences were sufficient to induce a differential bone response to unloading.

Our data asserted that even subtle differences in the genome can significantly alter basal bone morphology and response to unloading, demonstrating that even subtle interpopulation genomic differences may confound interpretations and conclusions drawn from two populations, even when these two populations are bred to generate the same phenotype.

Results from the dissertation identified 5 genes, CD44, NOD2, Fas, ESR1 and ESR2 as modulators of certain aspects of skeletal response to unloading, which in turn might potentially allow us to recognize and aid individuals predisposed to unloading induced bone loss. These five genes may also be harnessed as drug targets to treat bone disorders.

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Year

Entry

1999

Bi W, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B. Sox9 is required for cartilage formation. Nat Genet. May 1999;22(1):85-89.

2006

Sawakami K, Robling AG, Ai M, Pitner ND, Liu D, Warden SJ, Li J, Maye P, Rowe DW, Duncan RL, Warman ML, Turner CH. The Wnt co-receptor LRP5 is essential for skeletal mechanotransduction but not for the anabolic bone response to parathyroid hormone treatment. J Biol Chem. August 18, 2006;281(33):23698-23711.

2004

Somerville JM, Aspden RM, Armour KE, Armour KJ, Reid DM. Growth of C57Bl/6 mice and the material and mechanical properties of cortical bone from the tibia. Calcif Tiss Int. May 2004;74(5):469-475.

2010

Boskey AL, Coleman R. Aging and bone. J Dent Res. December 2010;89(2):1333-1348.

2002

Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, de Crombrugghe B. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell. January 11, 2002;108(1):17-29.