Zfp521 is a target gene and key effector of parathyroid hormone-related peptide signaling in growth plate chondrocytes.
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.
Correa
Diego
D
Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA.
Hesse
Eric
E
Seriwatanachai
Dutmanee
D
Kiviranta
Riku
R
Saito
Hiroaki
H
Yamana
Kei
K
Neff
Lynn
L
Atfi
Azeddine
A
Coillard
Lucie
L
Sitara
Despina
D
Maeda
Yukiko
Y
Warming
Soren
S
Jenkins
Nancy A
NA
Copeland
Neal G
NG
Horne
William C
WC
Lanske
Beate
B
Baron
Roland
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006132:Growth Plate / Q000378:metabolism / Q000473:pathology*; D006655:Histone Deacetylases / Q000378:metabolism; D006984:Hypertrophy; D051379:Mice; D018345:Mice, Knockout; D010012:Osteogenesis / Q000187:drug effects; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism* / Q000494:pharmacology; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism*
D015415:Biomarkers; D050659:Core Binding Factor Alpha 1 Subunit; C472572:Evi3 protein, mouse; D044162:Parathyroid Hormone-Related Protein; D012097:Repressor Proteins; C493716:Runx2 protein, mouse; D014157:Transcription Factors; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases