Dexamethasone inhibits and thyroid hormone promotes differentiation of mouse chondrogenic ATDC5 cells.
The effects of glucocorticoid (GC) excess, thyrotoxicosis, and hypothyroidism on linear growth indicate that growth plate chondrocytes are exquisitely sensitive to GC and thyroid hormone (T(3)). Murine ATDC5 cells undergo chondrogenesis in vitro and were used to evaluate the effects of dexamethasone (Dex) and T(3) on cell proliferation and differentiation. Immature and differentiated ATDC5 cells expressed glucocorticoid and T(3)-receptor mRNAs. Cells proliferated and organized into cartilage-like nodules after 7 days. Chondrocyte maturation progressed over 9-40 days, with increasing alkaline phosphatase (ALP) activity, secretion of an Alcian blue-positive matrix, and mineralization of cartilage-like nodules. Dex reduced cell number over the 40 day period, causing inhibition of ALP activity and matrix production with failure of mineralization. Following withdrawal of Dex, chondrocytes proliferated and re-entered the differentiation and mineralization program, indicating that GC inhibition of chondrogenesis is reversible. In contrast, T(3) reduced cell proliferation, but induced ALP activity and increased matrix secretion earlier than in control cultures. Thus, GCs and T(3) regulate growth plate chondrocyte differentiation by distinct mechanisms. GCs arrest cell proliferation, differentiation, and cartilage mineralization and maintain chondrocyte precursors in a state of quiescence with the capacity to re-enter chondrogenesis. T(3) inhibits cell proliferation but accelerates differentiation to stimulate chondrogenesis.
Siebler
T
T
Department of Endocrinology, Christie Hospital NHS Trust, Manchester, UK.
Robson
H
H
Shalet
S M
SM
Williams
G R
GR
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology*; D007150:Immunohistochemistry; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics; D011988:Receptors, Thyroid Hormone / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014284:Triiodothyronine / Q000494:pharmacology*
D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D003907:Dexamethasone