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.
Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA.
Diego
D
Correa
Eric
E
Hesse
Dutmanee
D
Seriwatanachai
Riku
R
Kiviranta
Hiroaki
H
Saito
Kei
K
Yamana
Lynn
L
Neff
Azeddine
A
Atfi
Lucie
L
Coillard
Despina
D
Sitara
Yukiko
Y
Maeda
Soren
S
Warming
Nancy A
NA
Jenkins
Neal G
NG
Copeland
William C
WC
Horne
Beate
B
Lanske
Roland
R
Baron
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