title: Aged male rats regenerate cortical bone with reduced osteocyte density and reduced secretion of nitric oxide after mechanical stimulation.
abstract: Mechanical loading is integral to the repair of bone damage. Osteocytes are mechanosensors in bone and participate in signaling through gap junction channels, which are primarily comprised of connexin 43 (Cx43). Nitric oxide (NO) and prostaglandin E2 (PGE2) have anabolic and catabolic effects on bone, and the secretion of these molecules occurs after mechanical stimulation. The effect of age on the repair of bone tissue after damage and on the ability of regenerated bone to transduce mechanical stimulation into a cellular response is unexplored. The goal of this study was to examine (1) osteocytes and their mineralized matrix within regenerated bone from aged and mature animals and (2) the ability of regenerated bone explants from aged and mature animals to transduce cyclic mechanical loading into a cellular response through NO and PGE2 secretion. Bilateral cortical defects were created in the diaphysis of aged (21-month-old) or mature (6-month-old) male rats, and new bone tissue was allowed to grow into a custom implant of controlled geometry. Mineralization and mineral-to-matrix ratio were significantly higher in regenerated bone from aged animals, while lacunar and osteocyte density and phosphorylated (pCx43) and total Cx43 protein were significantly lower, relative to mature animals. Regenerated bone from mature rats had increased pCx43 protein and PGE2 secretion with loading and greater NO secretion relative to aged animals. Reduced osteocyte density and Cx43 in regenerated bone in aged animals could limit the establishment of gap junctions as well as NO and PGE2 secretion after loading, thereby altering bone formation and resorption in vivo.
authors.affiliation: Orthopaedic Research Laboratories, University of Michigan, Biomedical Science Research Building, 109 Zina Pitcher Place Bay 4888, Ann Arbor, MI, 48108, USA, speededj@med.umich.edu.
authors.forename: Danese M
authors.initials: DM
authors.lastname: Joiner
authors.forename: Riyad J
authors.initials: RJ
authors.lastname: Tayim
authors.forename: John-David
authors.initials: JD
authors.lastname: McElderry
authors.forename: Michael D
authors.initials: MD
authors.lastname: Morris
authors.forename: Steven A
authors.initials: SA
authors.lastname: Goldstein
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D001861:Bone Regeneration / Q000502:physiology*; D001842:Bone and Bones / Q000502:physiology; D002113:Calcification, Physiologic / Q000502:physiology*; D008297:Male; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*; D010011:Osteocytes / Q000166:cytology / Q000378:metabolism; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D013059:Spectrum Analysis, Raman; D013314:Stress, Mechanical; D055114:X-Ray Microtomography
chemical_list: D009569:Nitric Oxide