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1.  Cellular and Molecular Mechanisms of Synovial Joint and Articular Cartilage Formation 
Synovial joints and articular cartilage play crucial roles in skeletal function, but relatively little is actually known about their embryonic development. Here we first focused on the interzone, a thin mesenchymal cell layer forming at future joint sites that is widely thought to be critical for joint and articular cartilage development. To determine interzone cell origin and fate, we microinjected the vital fluorescent dye DiI at several peri-joint sites in chick limbs and monitored behavior and fate of labeled cells over time. Peri-joint mesenchymal cells located immediately adjacent to incipient joints migrated, became part of the interzone, and were eventually found in epiphyseal articular layer and joint capsule. Interzone cells isolated and reared in vitro expressed typical phenotypic markers, including GDF-5, Wnt-14 and CD-44, and differentiated into chondrocytes over time. To determine the molecular mechanisms of articular chondrocyte formation, we carried out additional studies on the ets transcription factor family member ERG and its alternatively-spliced variant C-1-1 that we previously found to be expressed in developing avian articular chondrocytes. We cloned the human counterpart of avian C-1-1 (ERGp55Δ81) and conditionally expressed it in transgenic mice under cartilage-specific Col2 gene promoter-enhancer control. The entire transgenic mouse limb chondrocyte population exhibited an immature articular-like phenotype and a virtual lack of growth plate formation and chondrocyte maturation compared to wild type littermate. Together, our studies reveal that peri-joint mesenchymal cells take part in interzone and articular layer formation, interzone cells can differentiate into chondrocytes, and acquisition of a permanent articular chondrocyte phenotype is aided and perhaps dictated by ets transcription factor ERG.
PMCID: PMC2697570  PMID: 16831907
Synovial joint formation; articular cartilage; progenitor stem cells; transcription factor ERG
2.  Synovial Joint Formation during Mouse Limb Skeletogenesis: Roles of Indian Hedgehog Signaling 
Indian hedgehog (Ihh) has been previously found to regulate synovial joint formation. To analyze mechanisms, we carried out morphological, molecular and cell fate map analyses of interzone and joint development in wild type and Ihh−/− mouse embryo long bones. We found that Ihh−/− cartilaginous digit anlagen remained fused and lacked interzones or mature joints, whereas wrist skeletal elements were not fused but their joints were morphologically abnormal. E14.5 and E17.5 wild type digit and ankle anlagen expressed hedgehog target genes including Gli1 and Gli2 and interzone-associated genes including Gdf5, Erg and tenascin-C, but expression of all these genes was barely detectable in mutant joints. For cell fate map analysis of joint progenitor cells, we mated Gdf5-Cre+/−/Rosa R26R+/− double transgenic mice with heterozygous Ihh+/− mice and monitored reporter β-galactosidase activity and gene expression in triple-transgenic progeny. In control Gdf5-Cre+/−/R26R+/−/Ihh+/− limbs, reporter-positive cells were present in developing interzones, articulating layers and synovial lining tissue and absent from underlying growth plates. In mutant Gdf5-Cre+/−/R26R+/−/Ihh−/− specimens, reporter-positive cells were present also. However, the cells were mostly located around the prospective and uninterrupted digit joint sites and, interestingly, still expressed Erg, tenascin-C and Gdf5. Topographical analysis revealed that interzone and associated cells were not uniformly distributed, but were much more numerous ventrally. A similar topographical bias was seen for cavitation process and capsule primordia formation. In sum, Ihh is a critical and possibly direct regulator of joint development. In its absence, distribution and function of Gdf5-expressing interzone-associated cells are abnormal, but their patterning at prospective joint sites still occurs. The joint-forming functions of the cells appear to normally involve a previously unsuspected asymmetric distribution along the ventral-to-dorsal plane of the developing joint.
PMCID: PMC2673545  PMID: 18083924
synovial joint patterning; limb skeletogenesis; Indian hedgehog; interzone; joint progenitor cells; hedgehog signaling; Gli proteins; transcription factor Erg

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