The Deletion of Hdac4 in Mouse Osteoblasts Influences Both Catabolic and Anabolic Effects in Bone

Teruyo Nakatani, Tiffany Chen, Joshua Johnson, Jennifer J. Westendorf, Nicola Partridge

Research output: Contribution to journalArticle

Abstract

Histone deacetylase 4 (Hdac4) is known to control chondrocyte hypertrophy and bone formation. We have previously shown that parathyroid hormone (PTH) regulates many aspects of Hdac4 function in osteoblastic cells in vitro; however, in vivo confirmation was previously precluded by preweaning lethality of the Hdac4-deficient mice. To analyze the function of Hdac4 in bone in mature animals, we generated mice with osteoblast lineage-specific knockout of Hdac4 (Hdac4ob-/-) by crossing transgenic mice expressing Cre recombinase under the control of a 2.3-kb fragment of the Col1a1 promoter with mice bearing loxP-Hdac4. The Hdac4ob-/- mice survive to adulthood and developed a mild skeletal phenotype. At age 12 weeks, they had short, irregularly shaped and stiff tails due to smaller tail vertebrae, with almost no growth plates. The tibial growth plate zone was also thinned, and Mmp13 and Sost mRNAs were increased in the distal femurs of Hdac4ob-/- mice. Immunohistochemistry showed that sclerostin was elevated in Hdac4ob-/- mice, suggesting that Hdac4 inhibits its gene and protein expression. To determine the effect of PTH in these mice, hPTH (1-34) or saline were delivered for 14 days with subcutaneously implanted devices in 8-week-old female Hdac4ob-/- and wild-type (Hdac4fl/fl) mice. Serum CTX, a marker of bone resorption, was increased in Hdac4ob-/- mice with or without PTH treatment. Tibial cortical bone volume/total volume (BV/TV), cortical thickness (Ct.Th), and relative cortical area (RCA) were decreased in Hdac4ob-/- mice, but PTH caused no further decrease in Hdac4ob-/- mice. Tibial trabecular BV/TV and thickness were not changed significantly in Hdac4ob-/- mice but decreased with PTH treatment. These results indicate that Hdac4 inhibits bone resorption and has anabolic effects via inhibiting Mmp13 and Sost/sclerostin expression. Hdac4 influences cortical bone mass and thickness and knockout of Hdac4 prevents the catabolic effect of PTH in cortical bone.

Original languageEnglish (US)
JournalJournal of Bone and Mineral Research
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Anabolic Agents
Osteoblasts
Histone Deacetylases
Bone and Bones
Parathyroid Hormone
Growth Plate
Bone Resorption
Tail
Mouse Hdac5 protein
Teriparatide
Chondrocytes
Osteogenesis
Femur
Hypertrophy
Transgenic Mice
Spine
Immunohistochemistry
Phenotype
Gene Expression

Keywords

  • CATABOLIC EFFECTS OF PTH
  • CORTICAL BONE
  • HDAC4
  • OSTEOBLASTS
  • SCLEROSTIN

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

The Deletion of Hdac4 in Mouse Osteoblasts Influences Both Catabolic and Anabolic Effects in Bone. / Nakatani, Teruyo; Chen, Tiffany; Johnson, Joshua; Westendorf, Jennifer J.; Partridge, Nicola.

In: Journal of Bone and Mineral Research, 01.01.2018.

Research output: Contribution to journalArticle

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