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  • Paper Report
  • Open Access

BMP-2 induces osteoblast apoptosis mediated by PKC

  • 1
Arthritis Research & Therapy20024:74601

  • Received: 16 January 2002
  • Accepted: 25 January 2002
  • Published:


  • apoptosis
  • BMP-2
  • osteoblasts
  • PKC
  • TGF-?


Apoptosis of osteoblasts is a key to controlling osteoblast life span and bone formation, in addition to differentiation of progenitor cells. There are two types of regulators of osteoblast apoptosis: osteotropic hormones and local regulatory cytokines, such as tumor necrosis factor-a, interleukin-1 and -6, insulin-like growth factor-1, and fibroblast growth factor. Although it is well known that bone morphogenic proteins (BMPs) play a pivotal role in the commitment and differentiation of osteoblastic lineage, their role in apoptosis induction remains unknown.

Significant findings

BMP-2 promotes apoptosis in primary human calvariae and immortalized neonatal osteoblasts, while TGF-? inhibits apoptosis. BMP-2 increases the release of mitochondrial cytochrome c to the cytosol, the Bax/Bcl-2 ratio, and caspase-9, -3, -6, and -7 activity. When mutant Smad-1 is transfected in a dominant-negative fashion BMP-2-induced expression of osteoblast transcription factor Runx2 is downregulated, whereas the caspase activation and apoptosis is not affected. BMP-2 upregulates PKC activity and its inhibitor blocks osteoblasts-apoptosis induced by BMP-2, indicating that the proapoptotic effect of BMP-2 is PKC-dependent.


A novel role for BMP-2 in the induction of apoptosis in human osteoblasts has been demonstrated, although the ability to induce apoptosis by BMP-2 was not compared with other pro-inflammatory cytokines. The signaling pathway leading to apoptosis induction is not dependent on Smad, which is necessary for BMP-2-induced osteoblast differentiation, but on PKC. Given that the regulation of apoptosis in osteoblasts is pivotal to the control of bone formation, the results introduce a possibility that one can selectively modulate the BMP-2/apoptosis pathway without affecting osteoblast differentiation. It would be of interest to know whether apoptosis induced by proinflammatory cytokines other than BMP-2 can be inhibited by a selective PKC inhibitor.


TUNEL-staining, in vitro enzyme activity measurements, western blot, in vitro transfection

Additional information

Authors’ Affiliations

Dept. of Internal Medicine, Saitama Medical Center, Saitama Medical School, Saitama, Japan


  1. Hay E, Lemonnier J, Fromigue O, Marie PJ: Bone morphogenetic protein-2 promotes osteoblast apoptosis through a Smad-independent, protein kinase C-dependent signaling pathway. J Biol Chem. 2001, 276: 29028-29036.PubMedView ArticleGoogle Scholar


© Biomed Central Ltd 2002