TY - JOUR
T1 - Zfp521 is a target gene and key effector of parathyroid hormone-related peptide signaling in growth plate chondrocytes
AU - Correa, Diego
AU - Hesse, Eric
AU - Seriwatanachai, Dutmanee
AU - Kiviranta, Riku
AU - Saito, Hiroaki
AU - Yamana, Kei
AU - Neff, Lynn
AU - Atfi, Azeddine
AU - Coillard, Lucie
AU - Sitara, Despina
AU - Maeda, Yukiko
AU - Warming, Soren
AU - Jenkins, Nancy A.
AU - Copeland, Neal G.
AU - Horne, William C.
AU - Lanske, Beate
AU - Baron, Roland
N1 - Funding Information:
We thank Dr. B. Lee for MCT cells, Dr. E. Schipani for the PTHR1 – HKrk-H223R transgenic mice, Dr. A. Broadus for the PTHrP −/− mice, Dr. A. Lassar for HDAC4 and GAPDH siRNA plasmids, Dr. F. Long for the Col II-Cre mice, and Dr. H. Kronenberg for helpful discussion. Support was provided in part by National Institutes of Health-NIAMS grants AR048218 (R.B.) and AR050560 (B.L.). Additional support was provided by NIH training grant GM07527 (D.C.), the George Robert Pfeiffer Fellowship from the Gustavus and Louise Pfeiffer Research Foundation (D.C.), the Deutsche Forschungsgemeinschaft (E.H., HE 5208/1-1), the Gideon & Sevgi Rodan Fellowship from the International Bone and Mineral Society (E.H. and R.K.), the Academy of Finland (R.K.), and the Harvard School of Dental Medicine Dean's Scholars Award (E.H.).
PY - 2010/10/19
Y1 - 2010/10/19
N2 - In the growth plate, the interplay between parathyroid hormone-related peptide (PTHrP) and Indian hedgehog (Ihh) signaling tightly regulates chondrocyte proliferation and differentiation during longitudinal bone growth. We found that PTHrP increases the expression of Zfp521, a zinc finger transcriptional coregulator, in prehypertrophic chondrocytes. Mice with chondrocyte-targeted deletion of Zfp521 resembled PTHrP-/- and chondrocyte-specific PTHR1-/- mice, with decreased chondrocyte proliferation, early hypertrophic transition, and reduced growth plate thickness. Deleting Zfp521 increased expression of Runx2 and Runx2 target genes, and decreased Cyclin D1 and Bcl-2 expression while increasing Caspase-3 activation and apoptosis. Zfp521 associated with Runx2 in chondrocytes, antagonizing its activity via an HDAC4-dependent mechanism. PTHrP failed to upregulate Cyclin D1 and to antagonize Runx2, Ihh, and collagen X expression when Zfp521 was absent. Thus, Zfp521 is an important PTHrP target gene that regulates growth plate chondrocyte proliferation and differentiation.
AB - In the growth plate, the interplay between parathyroid hormone-related peptide (PTHrP) and Indian hedgehog (Ihh) signaling tightly regulates chondrocyte proliferation and differentiation during longitudinal bone growth. We found that PTHrP increases the expression of Zfp521, a zinc finger transcriptional coregulator, in prehypertrophic chondrocytes. Mice with chondrocyte-targeted deletion of Zfp521 resembled PTHrP-/- and chondrocyte-specific PTHR1-/- mice, with decreased chondrocyte proliferation, early hypertrophic transition, and reduced growth plate thickness. Deleting Zfp521 increased expression of Runx2 and Runx2 target genes, and decreased Cyclin D1 and Bcl-2 expression while increasing Caspase-3 activation and apoptosis. Zfp521 associated with Runx2 in chondrocytes, antagonizing its activity via an HDAC4-dependent mechanism. PTHrP failed to upregulate Cyclin D1 and to antagonize Runx2, Ihh, and collagen X expression when Zfp521 was absent. Thus, Zfp521 is an important PTHrP target gene that regulates growth plate chondrocyte proliferation and differentiation.
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U2 - 10.1016/j.devcel.2010.09.008
DO - 10.1016/j.devcel.2010.09.008
M3 - Article
C2 - 20951345
AN - SCOPUS:77957883340
SN - 1534-5807
VL - 19
SP - 533
EP - 546
JO - Developmental Cell
JF - Developmental Cell
IS - 4
ER -