Retinoic acid receptors are required for skeletal growth, matrix homeostasis and growth plate function in postnatal mouse.
The retinoic acid receptors alpha, beta and gamma (RARalpha, RARbeta and RARgamma) are nuclear hormone receptors that regulate fundamental processes during embryogenesis, but their roles in skeletal development and growth remain unclear. To study skeletal-specific RAR function, we created conditional mouse mutants deficient in RAR expression in cartilage. We find that mice deficient in RARalpha and RARgamma (or RARbeta and RARgamma) exhibit severe growth retardation obvious by about 3 weeks postnatally. Their growth plates are defective and, importantly, display a major drop in aggrecan expression and content. Mice deficient in RARalpha and RARbeta, however, are virtually normal, suggesting that RARgamma is essential. In good correlation, we find that RARgamma is the most strongly expressed RAR in mouse growth plate and its expression characterizes the proliferative and pre-hypertrophic zones where aggrecan is strongly expressed also. By being avascular, those zones lack endogenous retinoids as indicated by previous RARE reporter mice and our direct biochemical measurements and thus, RARgamma is likely to exert ligand-less repressor function. Indeed, our data indicate that: aggrecan production is enhanced by RARgamma over-expression in chondrocytes under retinoid-free culture conditions; production is further boosted by co-repressor Zac1 or pharmacologic agents that enhance RAR repressor function; and RAR/Zac1 function on aggrecan expression may involve Sox proteins. In sum, our data reveal that RARs, and RARgamma in particular, exert previously unappreciated roles in growth plate function and skeletal growth and regulate aggrecan expression and content. Since aggrecan is critical for growth plate function, its deficiency in RAR-mutant mice is likely to have contributed directly to their growth retardation.
Williams
Julie A
JA
Department of Orthopaedic Surgery, Thomas Jefferson University College of Medicine, Philadelphia, PA 19107, USA.
Kondo
Naoki
N
Okabe
Takahiro
T
Takeshita
Nobuo
N
Pilchak
Diane M
DM
Koyama
Eiki
E
Ochiai
Takanaga
T
Jensen
Deborah
D
Chu
Mon-Li
ML
Kane
Maureen A
MA
Napoli
Joseph L
JL
Enomoto-Iwamoto
Motomi
M
Ghyselinck
Norbert
N
Chambon
Pierre
P
Pacifici
Maurizio
M
Iwamoto
Masahiro
M
D053674:Aggrecans / Q000378:metabolism; D000818:Animals; D001846:Bone Development; D001842:Bone and Bones / Q000002:abnormalities*; D002356:Cartilage / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000502:physiology; D005109:Extracellular Matrix / Q000502:physiology*; D005260:Female; D016147:Genes, Tumor Suppressor; D006132:Growth Plate / Q000002:abnormalities / Q000254:growth & development / Q000502:physiology; D006706:Homeostasis; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012176:Retinoids / Q000494:pharmacology / Q000502:physiology; D012863:Skeleton; D014157:Transcription Factors / Q000378:metabolism
D053674:Aggrecans; D018797:Cell Cycle Proteins; C498423:Plagl1 protein, mouse; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D014157:Transcription Factors