The perichondrium plays an important role in mediating the effects of TGF‐β1 on endochondral bone formation

Abstract

Endochondral bone formation is complex and requires the coordination of signals from several factors and multiple cell types. Thus, chondrocyte differentiation is regulated by factors synthesized by both chondrocytes and cells in the perichondrium. Previously, we showed that expression of a dominant-negative form of the transforming growth factor beta (TGF-beta) type II receptor in perichondrium/periosteum resulted in increased hypertrophic differentiation in growth plate chondrocytes, suggesting a role for TGF-beta signaling to the perichondrium in limiting terminal differentiation in vivo. Using an organ culture model, we later demonstrated that TGF-beta1 inhibits chondrocyte proliferation and hypertrophic differentiation by two separate mechanisms. Inhibition of hypertrophic differentiation was shown to be dependent on Parathyroid hormone-related peptide (PTHrP) and expression of PTHrP mRNA was stimulated in the perichondrium after treatment with TGF-beta1. In this report, the hypothesis that the perichondrium is required for the effects of TGF-beta1 on growth and/or hypertrophic differentiation in mouse metatarsal organ cultures is tested. Treatment with TGF-beta1 inhibited expression of type X collagen mRNA in metatarsal cultures with the perichondrium intact. In contrast, hypertrophic differentiation as measured by expression of Type X collagen was not inhibited by TGF-beta1 in perichondrium-free cultures. TGF-beta1 added to intact cultures inhibited BrdU incorporation in chondrocytes and increased incorporation in the perichondrium; however, TGF-beta1 treatment stimulated chondrocyte proliferation in metatarsals from which the perichondrium had been enzymatically removed. These results suggest that the TGF-beta1-mediated regulation of both chondrocyte proliferation and hypertrophic differentiation is dependent upon the perichondrium. Thus, one or several factors from the perichondrium might mediate the way chondrocytes respond to TGF-beta1.

Characterization of two new zebrafish members of the hedgehog family: Atypical expression of a zebrafish indian hedgehog gene in skeletal elements of both endochondral and dermal origins

“…These observations are, however, contradictory to previous studies that showed that col10a1 expression is excluded from the perichondrium of developing mouse long bones (Fang and Hall, 1997;Javidan and Schilling, 2004). and that signals originating from the perichondrium negatively regulate chondrocyte maturation, and should therefore negatively regulate col10a1 expression (Long and Linsenmayer, 1998;Alvarez et al, 2001). The expression of col10a1 in osteoblast-like cells could reflect secondary chondrogenesis that occurs at the level of the articular surface of several craniofacial bones (Fang and Hall, 1997;Buxton et al 2003).…”

Inhibition of ALK5 Signaling Induces Physeal Dysplasia in Rats

“…IHH regulates the pace of chondrocytic differentiation (Van der Eerden et al, 2003). IHH has been proposed to stimulate PTHrP expression in the perichondrium in a negative feedback loop, and has several important functions including stimulation of chondrocyte proliferation, regulation of chondrocytic hypertrophy, inhibition of differentiation and stimulation of physeal stem cells in the reserve zone (Alvarez et al, 2001(Alvarez et al, , 2002. At least some of these functions are independent of PTHrP signaling.…”

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

“…TGFb signaling controls longitudinal bone growth through inhibition of chondrocyte terminal differentiation and maintenance of the proliferating chondrocyte pool (Serra et al 1997;Alvarez et al 2001;Yang et al 2001;Alvarez and Serra 2004). Consequently, conditional inactivation of Tgfbr2 or Tgfbr1, which leads to ablation of TGF-b signaling, results in severe shortening of the limbs among other skeletal manifestations (Baffi et al 2004;Seo and Serra 2007;Matsunobu et al 2009;Hiramatsu et al 2011).…”