Research Agenda
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Human genetic studies on HR-pQCT derived specific cortical and trabecular bone parameters will likely identify novel osteoporosis drug targets.
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Further technical improvements, including higher spatial
The interior structures of bone were examined beginning in the late 17th century, with Crisóstomo Martinez characterizing trabecular bone [1] and Clopton Havers discovering osteonal (Haversian) canals [2]. Studying dynamic aspects of bone metabolism became possible during the 1950s with autoradiography of bone-seeking radioisotopes [3] using undecalcified bone sections [4] and the fluorescent microscopy of tetracyclines [5], [6]. Development of techniques involving iliac crest biopsies examined
Although attention was focused on trabecular bone loss for many years, several scientists emphasized the importance of maintaining cortical bone mass for preventing osteoporotic fractures [4], [11]. The laboratory of Jonathan Reeve described histological analyses of femoral neck bone and they concluded in 2001 that there is no difference in trabecular bone area between cases of hip fracture and age and sex-matched controls. Rather, a loss of cortical bone thickness and increased porosity is a
Introduction of high resolution X-Ray Computed Tomography scanners after 2000 revolutionized examination and understanding of cortical bone dynamics [20]. Bones from rodent pharmacology studies and genetically-modified mouse models are now routinely analyzed by μCT for bone and marrow cavity areas, cortical thickness, cortical porosity, moments of inertia and tissue volumetric BMD. In addition to pure cortical bone sites, μCT analyses of rodent femoral neck and the vertebral body cortical shell
With certain caveats, rodent bone biology mimics human skeletal genetic and metabolic bone diseases, including responses to therapies, and rodents are extensively employed as osteoporosis research models. Nonetheless, several aspects of cortical bone development in rodents are poorly understood by many researchers and appreciation of these bone modeling processes is helpful. The following paragraphs summarize knowledge of both longitudinal and radial growth, and formation of cortical bone at
Reflecting the complex origins of its formation, cortical bone is structurally extremely heterogeneous. Bone viewed in histological sections under light or fluorescent microscopy, or from radiographic, DXA or CT X-ray images, generally appears homogeneous. Depending upon resolution, vascular canals and osteonal lacunae and canaliculi may be observed. However, little structural variability is observed in different quadrants and between periosteal and endocortical regions. In contrast, detailed
Twin and family studies have revealed that genetic factors can explain up to 85% of the variation in peak areal BMD as analyzed by 2-dimensional DXA [62], [63]. Since 2007, several genome-wide association studies (GWAS) for osteoporosis and related traits have identified multiple common variants associated with BMD, highlighting biologic pathways that influence areal BMD [64], [65], [66], [67], [68]. Although areal BMD is the most clinical useful measure for diagnosing bone fragility
WNT signaling pathways, involving 19 secreted WNTs, LRP4,5,6 co-receptors and extracellular inhibitors SFRP4, DKK1 and sclerostin, have major roles in bone metabolism [75]. The GWAS identification of a genetic signal for both cortical bone thickness and the clinical fracture endpoint in the WNT16 locus was followed by translational functional validation studies in mice and thorough cellular and molecular studies, unravelling a completely new mechanism for the regulation of cortical bone
Although periostin (Postn) is a widely expressed extracellular matrix protein with multiple activities, the highest expression is observed in cortical bone and periosteal tissue [87]. A crucial role of periostin in cortical bone is supported by observations that Postn knockout mice have low cortical bone mass resulting from reduced periosteal bone formation *[85], *[87], [88]. An effect of periostin in cortical but not trabecular bone homeostasis is further indicated by the finding that
Secreted frizzled related protein 4 (SFRP4) is a secreted Frizzled decoy receptor that binds WNTs to prevent their activation of Frizzled receptors. SFRP4 mutations cause Pyle's disease (OMIM 265900) [95], [96], *[97], with radiographs showing thin cortices in long bones, elevated trabecular bone mass, and wide metaphyseal bone (Erlenmeyer Flask deformity, EFD). The identical phenotypes occur in Sfrp4 KO mice *[85], *[97], [98] while overexpression of Sfrp4 results in low trabecular bone mass
Patients with Jansens's metaphyseal chondrodysplasia (OMIM 156400), resulting from ligand-independent activating mutations in the parathyroid hormone 1 receptor (PTH1R), suffer from hypercalcemia, hypophosphatemia, low circulating PTH levels, cortical bone erosion, and rickets-like metaphyseal dysplasia involving growth plate defects leading to dwarfism [101], [102]. Knockout of mouse Pth1r results in embryonic lethality [103] but a transgenic mouse model with expression of the constitutively
Advances in whole genome and whole exome sequencing continue to identify genes responsible for human genetic skeletal diseases and an update to the 2015 Skeletal Nosology database [106] is expected during 2018. Extremely high bone mass in humans can result from unidentified mutations [107], [108] and the genes responsible are likely to be identified during the next few years.
Great progress has been made during the past decade understanding the important contributions of cortical bone structure to skeletal strength and fracture resistance [109], [110], [111] and the genes involved in the growth (modeling), turnover (remodeling), microarchitecture and biomechanics of cortical bone. Continued advances are expected this next decade.
This study was supported by funding from the Swedish Research Council (grant 2016-01001), ALF/LUA research grant from the Sahlgrenska University Hospital, Lundberg Foundation, Torsten and Ragnar Söderberg's Foundation, Novo Nordisk Foundation, Knut and Alice Wallenberg Foundation. Human genetic studies on HR-pQCT derived specific cortical and trabecular bone parameters will likely identify novel osteoporosis drug targets. Further technical improvements, including higher spatialResearch Agenda