TY - JOUR
T1 - The Deletion of Hdac4 in Mouse Osteoblasts Influences Both Catabolic and Anabolic Effects in Bone
AU - Nakatani, Teruyo
AU - Chen, Tiffany
AU - Johnson, Joshua
AU - Westendorf, Jennifer J.
AU - Partridge, Nicola C.
N1 - Funding Information:
We thank Dr Eric Olson for kindly giving us the HDAC4 floxed mice (Hdac4fl/fl) and Dr Barbara Kream for giving us the Col2.3 1a(I)-Cre mice. We thank Dr Malvin Janal for advice on statistical analyses. This work was supported by NIH grant R01DK4720 and S10OD010751 to NCP. Authors’ roles: Study concept and design: TN and NCP. Data collection: TN, TC, and JJ. Data analysis: TN and NCP. Data interpretation: TN, JJW, and NCP. Drafting manuscript: TN, JJW, and NCP. Approving final version of manuscript: TN, TC, JJ, JJW, and NCP. TN takes responsibility for the integrity of the data analysis.
Funding Information:
This work was supported by NIH grant R01DK4720 and S10OD010751 to NCP.
Publisher Copyright:
© 2018 American Society for Bone and Mineral Research
PY - 2018/7
Y1 - 2018/7
N2 - 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 (Hdac4 ob-/- ) 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 Hdac4 ob-/- 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 Hdac4 ob-/- mice. Immunohistochemistry showed that sclerostin was elevated in Hdac4 ob-/- 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 Hdac4 ob-/- and wild-type (Hdac4 fl/fl ) mice. Serum CTX, a marker of bone resorption, was increased in Hdac4 ob-/- 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 Hdac4 ob-/- mice, but PTH caused no further decrease in Hdac4 ob-/- mice. Tibial trabecular BV/TV and thickness were not changed significantly in Hdac4 ob-/- 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.
AB - 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 (Hdac4 ob-/- ) 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 Hdac4 ob-/- 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 Hdac4 ob-/- mice. Immunohistochemistry showed that sclerostin was elevated in Hdac4 ob-/- 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 Hdac4 ob-/- and wild-type (Hdac4 fl/fl ) mice. Serum CTX, a marker of bone resorption, was increased in Hdac4 ob-/- 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 Hdac4 ob-/- mice, but PTH caused no further decrease in Hdac4 ob-/- mice. Tibial trabecular BV/TV and thickness were not changed significantly in Hdac4 ob-/- 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.
KW - CATABOLIC EFFECTS OF PTH
KW - CORTICAL BONE
KW - HDAC4
KW - OSTEOBLASTS
KW - SCLEROSTIN
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U2 - 10.1002/jbmr.3422
DO - 10.1002/jbmr.3422
M3 - Article
C2 - 29544022
AN - SCOPUS:85046286014
SN - 0884-0431
VL - 33
SP - 1362
EP - 1375
JO - Journal of Bone and Mineral Research
JF - Journal of Bone and Mineral Research
IS - 7
ER -