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What are mesenchymal precursor (stem) cells doing in rheumatoid arthritis joints?
Genes implicated in limb development and bone and joint formation,1,2 particularly members of the segment polarity family that encode components of the hedgehog and wingless/Wnt signalling pathways, have recently been identified in inflamed synovial tissues,3,4 prompting speculation about their role in the pathogenesis of rheumatoid arthritis (RA) (this issue, 6). In the limb bud of the embryo these genes are associated with primitive mesenchymal cells, which can be identified by their expression of heterodimeric surface membrane molecules that bind members of the transforming growth factor β super family, including bone morphogenetic protein receptors (BMPR), endoglin, anaplastic lymphoma kinase 1, and transforming growth factor β receptors.5,6 Postnatal bone marrow has similar mesenchymal progenitor cells (MPC) that provide the reticular stroma which supports haemopoiesis, and when appropriately stimulated MPC can give rise to bone, cartilage, fat, muscle, or fibrous tissues.6,7 RA synovium also contains cells with phenotypic and functional characteristics of MPC.8,9
ORIGINS OF SYNOVIAL MPC
The primordial appendicular skeleton begins as a condensed rod of primitive MPC that develop into articular structures.1 Among isolated normal rabbit and human synovial fibroblasts there is a minority population of cells that can be induced into osteogenic, chondrogenic, and adipogenic pathways, suggesting that a few undifferentiated MPC are normally present in synovial tissues.10,11 Their numbers are greatly increased in RA synovial tissues; 5–10 times more BMPR+ cells are identified in the intimal lining,12 and specific members of the Wnt family (5a and 13) are preferentially expressed in suspensions of whole synovium.3 Such findings may reflect either an expansion of a local population of MPC or a migration of MPC from the marrow into the inflamed joint. Both scenarios assume that the disease process …