Cytokines, osteoprotegerin, and RANKL in vitro and histomorphometric indices of bone turnover in patients with different bone diseases

J Bone Miner Res. 2003 Mar;18(3):529-38. doi: 10.1359/jbmr.2003.18.3.529.


Cytokines are supposed to play an essential role in the regulation of the bone metabolic unit. However, information on cytokine production of primary human osteoblasts from patients with metabolic bone disease is scarce, and few attempts have been made to correlate such data to histomorphometric parameters of individual patients. We investigated 11 patients with metabolic bone disease referred to our outpatient department for bone biopsy and analyzed interleukin (IL)-1, IL-6, and TNF-alpha protein release and gene expression in primary osteoblast cultures. Compared with four controls, five patients showed normal cytokine protein release, whereas six patients showed much higher levels of interleukin-6 (26-fold) and TNF-alpha (84-fold). All three cytokines were strongly correlated concerning gene expression and/or protein levels (r = 0.72-0.96). Histomorphometric analysis of the bone samples showed that eroded surface (ES/BS) as a parameter of bone resorption was significantly associated with TNF-a. In addition, RANKL gene expression was positively associated with ES/BS and osteoclast surface (Oc.S/BS). Finally, the formation parameters osteoid volume and osteoid surface were negatively associated with TNF-alpha. In conclusion, in an in vitro-ex vivo model of bone cells obtained from a group of 11 patients with different forms of metabolic bone disease, cytokine release in conditioned medium was significantly associated with bone resorption and bone formation, as quantified by histomorphometry. TNF-alpha seemed to be the more important cytokine; its effect on bone resorption could be mediated by RANKL.

MeSH terms

  • Adult
  • Aged
  • Base Sequence
  • Bone Diseases / metabolism
  • Bone Diseases / physiopathology*
  • Bone Remodeling*
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Cytokines / physiology*
  • DNA Primers
  • Female
  • Gene Expression
  • Glycoproteins / genetics
  • Glycoproteins / physiology*
  • Humans
  • In Vitro Techniques
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / physiology*
  • Middle Aged
  • Osteoprotegerin
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Receptors, Tumor Necrosis Factor


  • Carrier Proteins
  • Cytokines
  • DNA Primers
  • Glycoproteins
  • Membrane Glycoproteins
  • Osteoprotegerin
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Tumor Necrosis Factor
  • TNFRSF11A protein, human
  • TNFRSF11B protein, human
  • TNFSF11 protein, human