title: Indian and sonic hedgehogs regulate synchondrosis growth plate and cranial base development and function.
abstract: The synchondroses consist of mirror-image growth plates and are critical for cranial base elongation, but relatively little is known about their formation and regulation. Here we show that synchondrosis development is abnormal in Indian hedgehog-null mice. The Ihh(-/-) cranial bases displayed reduced growth and chondrocyte proliferation, but chondrocyte hypertrophy was widespread. Rather than forming a typical narrow zone, Ihh(-/-) hypertrophic chondrocytes occupied an elongated central portion of each growth plate and were flanked by immature collagen II-expressing chondrocytes facing perichondrial tissues. Endochondral ossification was delayed in much of the Ihh(-/-) cranial bases but, surprisingly, was unaffected most posteriorly. Searching for an explanation, we found that notochord remnants near incipient spheno-occipital synchondroses at E13.5 expressed Sonic hedgehog and local chondrocytes expressed Patched, suggesting that Shh had sustained chondrocyte maturation and occipital ossification. Equally unexpected, Ihh(-/-) growth plates stained poorly with Alcian blue and contained low aggrecan transcript levels. A comparable difference was seen in cultured wild-type versus Ihh(-/-) synchondrosis chondrocytes. Treatment with exogenous Ihh did not fully restore normal proteoglycan levels in mutant cultures, but a combination of Ihh and BMP-2 did. In summary, Ihh is required for multiple processes during synchondrosis and cranial base development, including growth plate zone organization, chondrocyte orientation, and proteoglycan production. The cranial base appears to be a skeletal structure in which growth and ossification patterns along its antero-posterior axis are orchestrated by both Ihh and Shh.
authors.affiliation: Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, PA 19017, USA.
authors.forename: Blanche
authors.initials: B
authors.lastname: Young
authors.forename: Nancy
authors.initials: N
authors.lastname: Minugh-Purvis
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shimo
authors.forename: Benoit
authors.initials: B
authors.lastname: St-Jacques
authors.forename: Masahiro
authors.initials: M
authors.lastname: Iwamoto
authors.forename: Motomi
authors.initials: M
authors.lastname: Enomoto-Iwamoto
authors.forename: Eiki
authors.initials: E
authors.lastname: Koyama
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pacifici
mesh_terms: D053674:Aggrecans / Q000235:genetics; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000473:pathology; D020219:Chondrogenesis / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D005819:Genetic Markers; D006132:Growth Plate / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006984:Hypertrophy; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D009778:Occipital Lobe / Q000166:cytology; D010012:Osteogenesis / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019291:Skull Base / Q000166:cytology / Q000196:embryology* / Q000473:pathology
chemical_list: D053674:Aggrecans; D005819:Genetic Markers; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C465570:Shh protein, mouse; C514061:ihh protein, mouse