• Model Description

TghRANKL (Tg5519) mice carry the human RANKL (huRANKL) genomic region as transgene and overexpress huRANKL according to a physiologically relevant pattern of expression1. The overexpression of huRANKL in these animals results in the spontaneous development of early-onset osteoporosis characterized by lack of trabecular bone, destruction of the growth plate, increased osteoclastogenesis, bone marrow adiposity, increased bone remodeling and severe cortical bone porosity accompanied by decreased bone strength of similar severity in both sexes.

Figure 2: As osteoporosis is a “silent disease” TghRANKL animals develop normally and phenotypically they are very similar to wild type animals.

Histology

Histopathological characteristics of the osteoporotic phenotype in TghRANKL animals include loss of trabecular bone, bone marrow adiposity and severe cortical bone porosity as seen in H&E staining and increased osteoclastogenesis as seen in TRAP staining. All these characteristics closely resemble the pathological characteristics of human osteoporosis

Figure 3.

Preclinical Efficacy evaluation

Study design

Treatment starts at 4 weeks of age and is continued until the 10th week of age of the animals.

Read-out parameters

  • In vivo body weight measurements for the whole duration of the study as a measurement of the overall health status of the animals.
  • TRACP serum levels measurements as a marker of osteoclast activity at various time points
  • Histopathological evaluation to assess features of osteoporotic phenotype
  • Micro-CT analysis of femurs and evaluation of trabecular and cortical bone morphology.
  • Additional bone metabolism markers can be evaluated upon request

Figure 4: Representative images of TRAP stained femur sections showing dose depended reversal of the osteoportic phenotype of TghRANKL animals following anti-hRANKL treatment.

Figure 5: Representative microCT images showing dose depended reversal of the osteoportic phenotype of TghRANKL animals following anti-hRANKL treatment.

Figure 6: Representative graphs of TRACP levels after 2 weeks (up) or 6 weeks (down) of anti-hRANKL treatment. 2 weeks of treatment are enough to get clear evidence for the in vivo efficacy of your drug, while 6 weeks of treatmwnt further reveal the efficacy of lower doses. 

 

Bibliography
1. RinotasV, Niti A, Dacquin R, Bonnet N, Stolina M, Han CY, Kostenuik P, Jurdic P, Ferrari S and Douni E, 2014. "Novel Genetic Models of Osteoporosis by Overexpression of Human RANKL in Transgenic Mice". Journal of Bone and Mineral Research, May 2014, Volume 29, Issue 5, pages 1158–1169. (view article).
 
A paper describing the generation and characterization of the TghRANKL model of osteoporosis.

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