Suberoylanilide hydroxamic acid (SAHA; vorinostat) causes bone loss by inhibiting immature osteoblasts

Meghan E. McGee-Lawrence, Angela L. McCleary-Wheeler, Frank J. Secreto, David F. Razidlo, Minzhi Zhang, Bridget A. Stensgard, Xiaodong Li, Gary S. Stein, Jane B. Lian, Jennifer J Westendorf

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Histone deacetylase (Hdac) inhibitors are used clinically to treat cancer and epilepsy. Although Hdac inhibition accelerates osteoblast maturation and suppresses osteoclast maturation in vitro, the effects of Hdac inhibitors on the skeleton are not understood. The purpose of this study was to determine how the pan-Hdac inhibitor, suberoylanilide hydroxamic acid (SAHA; a.k.a. vorinostat or ZolinzaTM) affects bone mass and remodeling in vivo. Male C57BL/6J mice received daily SAHA (100mg/kg) or vehicle injections for 3 to 4weeks. SAHA decreased trabecular bone volume fraction and trabecular number in the distal femur. Cortical bone at the femoral midshaft was not affected. SAHA reduced serum levels of P1NP, a bone formation marker, and also suppressed tibial mRNA levels of type I collagen, osteocalcin and osteopontin, but did not alter Runx2 or osterix transcripts. SAHA decreased histological measures of osteoblast number but interestingly increased indices of osteoblast activity including mineral apposition rate and bone formation rate. Neither serum (TRAcP 5b) nor histological markers of bone resorption were affected by SAHA. P1NP levels returned to baseline in animals which were allowed to recover for 4weeks after 4weeks of daily SAHA injections, but bone density remained low. In vitro, SAHA suppressed osteogenic colony formation, decreased osteoblastic gene expression, induced cell cycle arrest, and caused DNA damage in bone marrow-derived adherent cells. Collectively, these data demonstrate that bone loss following treatment with SAHA is primarily due to a reduction in osteoblast number. Moreover, these decreases in osteoblast number can be attributed to the deleterious effects of SAHA on immature osteoblasts, even while mature osteoblasts are resistant to the harmful effects and demonstrate increased activity in vivo, indicating that the response of osteoblasts to SAHA is dependent upon their differentiation state. These studies suggest that clinical use of SAHA and other Hdac inhibitors to treat cancer, epilepsy or other conditions may potentially compromise skeletal structure and function.

Original languageEnglish (US)
Pages (from-to)1117-1126
Number of pages10
JournalBone
Volume48
Issue number5
DOIs
StatePublished - May 1 2011

Fingerprint

Osteoblasts
Bone and Bones
Histone Deacetylase Inhibitors
Osteogenesis
Epilepsy
Injections
Osteopontin
Histone Deacetylases
vorinostat
Bone Remodeling
Osteocalcin
Osteoclasts
Bone Resorption
Collagen Type I
Thigh
Cell Cycle Checkpoints
Serum
Inbred C57BL Mouse
Skeleton
Bone Density

Keywords

  • γH2AX
  • Hdac
  • Histone deacetylase inhibitor
  • Osteoblasts
  • Zolinza

ASJC Scopus subject areas

  • Physiology
  • Endocrinology, Diabetes and Metabolism
  • Histology

Cite this

McGee-Lawrence, M. E., McCleary-Wheeler, A. L., Secreto, F. J., Razidlo, D. F., Zhang, M., Stensgard, B. A., ... Westendorf, J. J. (2011). Suberoylanilide hydroxamic acid (SAHA; vorinostat) causes bone loss by inhibiting immature osteoblasts. Bone, 48(5), 1117-1126. https://doi.org/10.1016/j.bone.2011.01.007

Suberoylanilide hydroxamic acid (SAHA; vorinostat) causes bone loss by inhibiting immature osteoblasts. / McGee-Lawrence, Meghan E.; McCleary-Wheeler, Angela L.; Secreto, Frank J.; Razidlo, David F.; Zhang, Minzhi; Stensgard, Bridget A.; Li, Xiaodong; Stein, Gary S.; Lian, Jane B.; Westendorf, Jennifer J.

In: Bone, Vol. 48, No. 5, 01.05.2011, p. 1117-1126.

Research output: Contribution to journalArticle

McGee-Lawrence, ME, McCleary-Wheeler, AL, Secreto, FJ, Razidlo, DF, Zhang, M, Stensgard, BA, Li, X, Stein, GS, Lian, JB & Westendorf, JJ 2011, 'Suberoylanilide hydroxamic acid (SAHA; vorinostat) causes bone loss by inhibiting immature osteoblasts', Bone, vol. 48, no. 5, pp. 1117-1126. https://doi.org/10.1016/j.bone.2011.01.007
McGee-Lawrence ME, McCleary-Wheeler AL, Secreto FJ, Razidlo DF, Zhang M, Stensgard BA et al. Suberoylanilide hydroxamic acid (SAHA; vorinostat) causes bone loss by inhibiting immature osteoblasts. Bone. 2011 May 1;48(5):1117-1126. https://doi.org/10.1016/j.bone.2011.01.007
McGee-Lawrence, Meghan E. ; McCleary-Wheeler, Angela L. ; Secreto, Frank J. ; Razidlo, David F. ; Zhang, Minzhi ; Stensgard, Bridget A. ; Li, Xiaodong ; Stein, Gary S. ; Lian, Jane B. ; Westendorf, Jennifer J. / Suberoylanilide hydroxamic acid (SAHA; vorinostat) causes bone loss by inhibiting immature osteoblasts. In: Bone. 2011 ; Vol. 48, No. 5. pp. 1117-1126.
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