CD99 drives terminal differentiation of osteosarcoma cells by acting as a spatial regulator of ERK 1/2

Marika Sciandra, Maria Teresa Marino, Maria Cristina Manara, Clara Guerzoni, Maria Grano, Angela Oranger, Enrico Lucarelli, Pier Luigi Lollini, Barbara Dozza, Loredana Pratelli, Maria Flavia Di Renzo, Mario Paolo Colombo, Piero Picci, Katia Scotlandi

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


Differentiation therapy is an attractive treatment for osteosarcoma (OS). CD99 is a cell surface molecule expressed in mesenchymal stem cells and osteoblasts that is maintained during osteoblast differentiation while lost in OS. Herein, we show that whenever OS cells regain CD99, they become prone to reactivate the terminal differentiation program. In differentiating conditions, CD99-transfected OS cells express osteocyte markers, halt proliferation, and largely die by apoptosis, resembling the fate of mature osteoblasts. CD99 induces ERK activation, increasing its membrane-bound/cytoplasmic form rather than affecting its nuclear localization. Through cytoplasmic ERK, CD99 promotes activity of the main osteogenic transcriptional factors AP1 and RUNX2, which in turn enhance osteocalcin and p21WAF1/CIP1, leading to G 0/G1 arrest. These data underscore the alternative positions of active ERK into distinct subcellular compartments as key events for determining OS fate.

Original languageEnglish (US)
Pages (from-to)1295-1309
Number of pages15
JournalJournal of Bone and Mineral Research
Issue number5
StatePublished - May 2014


  • CD99
  • RUNX2
  • mapk signaling
  • osteoblast differentiation
  • osteosarcoma

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine


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