TGF-β type II receptor/MCP-5 axis: at the crossroad between joint and growth plate development.
Despite its clinical significance, the mechanisms of joint morphogenesis are elusive. By combining laser-capture microdissection for RNA sampling with microarrays, we show that the setting in which joint-forming interzone cells develop is distinct from adjacent growth plate chondrocytes and is characterized by downregulation of chemokines, such as monocyte-chemoattractant protein-5 (MCP-5). Using in vivo, ex vivo, and in vitro approaches, we show that low levels of interzone-MCP-5 are essential for joint formation and contribute to proper growth plate organization. Mice lacking the TGF-β-type-II-receptor (TβRII) in their limbs (Tgfbr2(Prx1KO)), which lack joint development and fail chondrocyte hypertrophy, show upregulation of interzone-MCP-5. In vivo and ex vivo blockade of the sole MCP-5 receptor, CCR2, led to the rescue of joint formation and growth plate maturation in Tgfbr2(Prx1KO) but an acceleration of growth plate mineralization in control mice. Our study characterized the TβRII/MCP-5 axis as an essential crossroad for joint development and endochondral growth.
Department of Pediatrics, University of North Carolina at Chapel Hill, NC 27599, USA.
Lara
L
Longobardi
Tieshi
T
Li
Timothy J
TJ
Myers
Lynda
L
O'Rear
Huseyin
H
Ozkan
Ying
Y
Li
Clara
C
Contaldo
Anna
A
Spagnoli
D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology / Q000196:embryology; D019902:Chondrocytes / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006132:Growth Plate / Q000166:cytology / Q000196:embryology*; D007596:Joints / Q000166:cytology / Q000196:embryology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
C491224:Ccl12 protein, mouse; D018945:Monocyte Chemoattractant Proteins; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II