Effects of Exogenous Lipopolysaccharide Exposure on Bone Outcomes in Rodent Models

Chronic low-grade inflammation has been identified as a potential contributor to the pathophysiology of osteoporosis. A key mediator may be lipopolysaccharide (LPS) released from gram-negative bacteria in the gut that can enter circulation stimulating an inflammatory response and upregulate bone resorption. Since rodent models mimic the loss of bone mineral density (BMD) and structure that occurs in humans, rodents offer an accelerated model for studying these inflammation-mediated changes. Therefore, the objective of this thesis was to characterize a rodent model of LPS-induced bone loss using repeated in vivo μCT scans to establish a time course effect of LPS longitudinally and for this purpose three studies were conducted. Study 1 & 2 were run simultaneously using the same control mice. Study 1 demonstrated that repeated irradiation had a negative impact on trabecular bone in both male and female CD-1 mice, while cortical bone was only negatively impacted in the females. In study 2, continuous delivery of exogenous LPS via osmotic pumps for 12 weeks elevated serum LPS in both male and female CD-1 mice but did not alter trabecular or cortical bone structure or BMD at any of the scanning timepoints. Results from Study 2 may in part have been influenced by the effects of repeated irradiation from the in vivo μCT scans at 4-week intervals for a total of 4 scans analyzed in Study 1. In study 3, a systematic review was conducted to better characterize a model of LPS induced bone loss and identify factors that may impact the effects of LPS on bone outcomes in rodent models. Regardless of study duration, exogenous LPS negatively impacted trabecular bone structure and BMD but not cortical bone structure, due to an upregulation in bone resorption. Together these data suggest that exogenous LPS can induce alterations in bone structure and BMD in rodent models, however a clearly defined model of exogenous LPS induced bone loss has yet to be fully characterized.

Year	Entry
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Year

Entry

2002

Halloran BP, Ferguson VL, Simske SJ, Burghardt A, Venton LL, Majumdar S. Changes in bone structure and mass with advancing age in the male C57BL/6J mouse. J Bone Miner Res. June 2002;17(6):1044-1050.

2010

Willinghamm MD, Brodt MD, Lee KL, Stephens AL, Ye J, Silva MJ. Age-related changes in bone structure and strength in female and male BALB/c mice. Calcif Tiss Int. June 2010;86(6):470-483.

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.

2004

Schuit SCE, van der Klift M, Weel AEAM, de Laet CEDH, Burger H, Seeman E, Hofman A, Uitterlinden AG, van Leeuwen JPTM, Pols HAP. Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study. Bone. January 2004;34(1):195-202.

2003

David V, Laroche N, Boudignon B, Lafage‐Proust M, Alexandre C, Ruegsegger P, Vico L. Noninvasive in vivo monitoring of bone architecture alterations in hindlimb‐unloaded female rats using novel three‐dimensional microcomputed tomography. J Bone Miner Res. September 2003;18(9):1622-1631.