title: Patterns of osteocytic endothelial nitric oxide synthase expression in the femoral neck cortex: differences between cases of intracapsular hip fracture and controls.
abstract: Evidence indicates that extensive amalgamation of adjacent resorbing osteons is responsible for destroying the microstructural integrity of the femoral neck's inferior cortex in osteoporotic hip fracture. Such osteonal amalgamation is likely to involve a failure to limit excessive resorption, but its mechanistic basis remains enigmatic. Nitric oxide (NO) inhibits osteoclastic bone destruction, and in normal bone cells its generation by endothelial nitric oxide synthase (eNOS, the predominant bone isoform) is enhanced by mechanical stimuli and estrogen, which both protect against fracture. To determine whether eNOS expression in osteocytes reflects their proposed role in regulating remodeling, we have examined patterns of osteocyte eNOS immunolabeling in the femoral neck cortex of seven cases of hip fracture and seven controls (females aged 68-96 years). The density of eNOS+ cells (mm(-2)) was 53% lower in the inferior cortex of the fracture cases (p < 0.0004), but was similar in the superior cortex. eNOS+ osteocytes were, on average, 22% further from their nearest blood supply, than osteocytes in general (p < 0.0001) and the nearest eNOS+ osteocyte was 57% further from its nearest canal surface (p < 0.0001). This differential distribution of eNOS+ osteocytes was significantly more pronounced in the cortices of fracture cases (p < 0.0001). We conclude that the normal regional and osteonal pattern of eNOS expression by osteocytes is disrupted in hip fracture, particularly at sites that are loaded most by physical activity. These results suggest that eNOS+ osteocytes may normally act as sentinels confining resorption within single osteons. A reduction in their number, coupled to an increase in their remoteness from canal surfaces, may thus permit the irreversible merging of resorbing osteons, and thus contribute to the marked increase in the fragility of osteoporotic bone.
authors.affiliation: Bone Research Group (MRC), Department of Medicine, University of Cambridge, UK. nl10003@medschl.cam.ac.uk
authors.forename: N
authors.initials: N
authors.lastname: Loveridge
authors.forename: S
authors.initials: S
authors.lastname: Fletcher
authors.forename: J
authors.initials: J
authors.lastname: Power
authors.forename: A M
authors.initials: AM
authors.lastname: Caballero-Alías
authors.forename: V
authors.initials: V
authors.lastname: Das-Gupta
authors.forename: N
authors.initials: N
authors.lastname: Rushton
authors.forename: M
authors.initials: M
authors.lastname: Parker
authors.forename: J
authors.initials: J
authors.lastname: Reeve
authors.forename: A A
authors.initials: AA
authors.lastname: Pitsillides
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D002452:Cell Count; D005260:Female; D005265:Femoral Neck Fractures / Q000201:enzymology* / Q000473:pathology; D005272:Femur Neck / Q000166:cytology / Q000201:enzymology*; D006621:Hip Joint / Q000166:cytology / Q000201:enzymology; D006801:Humans; D007150:Immunohistochemistry; D017746:Joint Capsule / Q000166:cytology / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III; D010011:Osteocytes / Q000201:enzymology*
chemical_list: C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III