EXPRESSION AND DISTRIBUTION OF TRANSFORMING-GROWTH-FACTOR-BETA ISOFORMS AND THEIR SIGNALING RECEPTORS IN GROWING HUMAN BONE

Transforming growth factors type beta (TGF-beta 1, -beta 2, and -beta 3) are potent stimulators of bone formation and have been shown to reg ulate chondrocyte, osteoblast, and osteoclast formation and function. However, the distribution of the different isoforms and their signalin g receptors in human hone in vivo has not previously been reported. Us ing samples of normal (neonatal rib) and pathological (osteophytic) de veloping human bene,,ve have investigated the expression of the differ ent TGF-beta isoforms and their signaling receptors (TGF-beta RI and R II) at the messenger ribonucleic acid (mRNA) and protein levels by in situ hybridization and immunolocalization to establish the sites of TG F-beta production and their possible sites of action during human bone development in vivo, AIL three TGF-beta isoforms and the receptors we re detected at sites of endochondral and intramembranous ossification. At sites of endochondral ossification, TGF-beta 2 was detected in ail zones of the cartilage, with the highest expression seen in the hyper trophic and mineralizing zones. TGF-beta 3 was detected in proliferati ve and hypertrophic zone chondrocytes, while TGF-beta 1 expression was restricted to the proliferative and upper hypertrophic zones. TGF-bet a RI and RII exhibited similar distributions with maximum expression i n the hypertrophic and mineralizing zones in the neonatal rib but in t he resting/proliferative zone in the developing osteophyte, At sites o f intramembranous ossification TGF-beta 3 was the most widely distribu ted isoform and shelved both matrix- and cell-associated staining. TGF -beta 2 and -beta 1 were expressed almost exclusively at sites of mine ralization, These observations demonstrate that the different TGF-beta isoforms and their receptors exhibit distinct but overlapping pattern s of expression, and support the hypothesis that they are involved in the regulation of endochondral and intramembranous ossification during human bone development in vivo, (Bone 23:95-102; 1998) (C) 1998 by El sevier Science Inc, All rights reserved.