Dysapoptosis of osteoblasts and osteocytes increases cancellous bone formation but exaggerates cortical porosity with age

Robert L. Jilka, Charles A. O'Brien, Paula K. Roberson, Lynda F. Bonewald, Robert S. Weinstein, Stavros C. Manolagas

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Skeletal aging is accompanied by decreased cancellous bone mass and increased formation of pores within cortical bone. The latter accounts for a large portion of the increase in nonvertebral fractures after age 65 years in humans. We selectively deleted Bak and Bax, two genes essential for apoptosis, in two types of terminally differentiated bone cells: the short-lived osteoblasts that elaborate the bone matrix, and the long-lived osteocytes that are immured within the mineralized matrix and choreograph the regeneration of bone. Attenuation of apoptosis in osteoblasts increased their working lifespan and thereby cancellous bone mass in the femur. In long-lived osteocytes, however, it caused dysfunction with advancing age and greatly magnified intracortical femoral porosity associated with increased production of receptor activator of nuclear factor-κB ligand and vascular endothelial growth factor. Increasing bone mass by artificial prolongation of the inherent lifespan of short-lived osteoblasts, while exaggerating the adverse effects of aging on long-lived osteocytes, highlights the seminal role of cell age in bone homeostasis. In addition, our findings suggest that distress signals produced by old and/or dysfunctional osteocytes are the culprits of the increased intracortical porosity in old age.

Original languageEnglish (US)
Pages (from-to)103-117
Number of pages15
JournalJournal of Bone and Mineral Research
Volume29
Issue number1
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Keywords

  • Apoptosis
  • aging
  • bone formation
  • cortical porosity
  • osteoblasts
  • osteocytes
  • rankl

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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