Although a histology core has been part of the MGH Endocrine Unit since 1997, the integration of histology with in vivo bone densitometry and ex vivo microtomographic imaging began with the creation of the Skeletal Phenotyping Core at the beginning of the current funding period (i.e. 2003). Since that time, this core has provided hierarchical assessment of musculoskeletal phenotypes in rodent models with genetic alterations, as well as dietary and pharmacologic interventions. The formation of the core has allowed efficient evaluation of tissue samples, both with regard to time and resources (e.g., microCT and histomorphometry assessments on the same specimen, leaving the contralateral side for alternative evaluations). Altogether the formation of the core has been highly effective in supporting the investigators in the Program Project, as evidenced by the number of specimens processed and number of manuscripts to which the core contributed. In the current renewal, we will maintain all of the current services and features of the core, and will add biomechanical testing to enhance the assessment of structure-function relationships in the various experimental models. In addition, the core will expand its histology services to include assessment of kidney specimens, as outlined in Project IV. In the current funding period, the core supported 4 of the 5 projects, whereas in the renewal, with an expansion of the use of in vivo models, the Tissue Phenotyping Core will support all 4 of the projects. Need for Integrated Musculoskeletal Evaluation: In the past 5 to 10 years, skeletal imaging in rodent models, particularly the murine models used in this Program Project, has improved markedly. Now, in addition to 2D radiographs and area! bone mineral density measurements, high-resolution desktop imaging systems are used routinely to assess bone microarchitecture during early development as well as post-natal growth (6). We have evaluated porous aluminum foams, human trabecular and cortical bone specimens, and a variety of excised bone specimens from different animals (whale, cow, rat, mouse, non-human primate, zebrafish), though much of our experience is with the murine skeleton (7-18). The role of uCT is expanding rapidly in biomedical research, as it provides a non-destructive, high-resolution, true 3D evaluation of bone volume fraction and microarchitecture. Moreover, recent advances allow assessment of the mineral density of the tissue being evaluated. The non-destructive nature of the technique means that following evaluation by uCT, specimens can be assessed by any number of alternative techniques, including standard histologic and histomorphometric assessment to gain information on the cellular composition and activity, in situ hybridization or immunohistochemistry to determine the patterns of gene expression, or biomechanical testing to determine bone strength. To fully understand the skeletal consequences of genetic alterations or pharmacologic interventions, it is critical to assess structure-function relationships at the molecular, organ and whole body levels. A key element to assessing skeletal "function" is biomechanical testing. Elegantly stated in the review by van der Meulen and colleagues, " the skeletal function integrity can only be assess by structural strength tests that measure how well the whole bone can bear load ? there is no alternative to testing whole bone strength, and conclusions regarding bone mechanical function based solely on geometry of bone mineral contact are inappropriate and likely misleading." (19). Biomechanical testing has been employed for decades to assess the determinants of bone strength and fragility. Yet, despite the known importance of this type of assay, along with wellestablished protocols, a recent editorial reported that less than 30% of experimental studies published in the main bone-oriented journals included whole bone strength testing (20). The authors argue that along with whole bone strength testing, morphology and microarchitecture measurements are essential to characterize skeletal mechanical competence. In this renewal, we proposed to add biomechanical testing, in particular vertebral compression and femoral 3-point bending, to the services offered by the Core facility. The overall significance of this core facility is that it provides investigators in the Program Project access to technologies that they would otherwise not have access to either because the equipment is very expensive (in the case of microCT) and/or special expertise is required for the conduct and interpretation of the assay (i.e., histology, histomorphometry, in situ hybridization, immunohistochemistry, biomechanical testing). Therefore, despite the scientific value that these measurements bring to research studies, it is clear that few individual investigators would themselves have access to this equipment and expertise. Moreover, by being operated as a core facility, these assessments can be conducted in well-organized fashion by a team of experienced personnel, with cost- and time-savings passed on to individual investigators.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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