Molecular mechanism of synovial joint site specification and induction in developing vertebrate limbs.

The vertebrate appendage comprises three primary segments, the stylopod, zeugopod and autopod, each separated by joints. The molecular mechanisms governing the specification of joint sites, which define segment lengths and thereby limb architecture, remain largely unknown. Existing literature suggests that reciprocal gradients of retinoic acid (RA) and fibroblast growth factor (FGF) signaling define the expression domains of the putative segment markers Meis1, Hoxa11 and Hoxa13. Barx1 is expressed in the presumptive joint sites. Our data demonstrate that RA-FGF signaling gradients define the expression domain of Barx1 in the first presumptive joint site. When misexpressed, Barx1 induces ectopic interzone-like structures, and its loss of function partially blocks interzone development. Simultaneous perturbations of RA-FGF signaling gradients result in predictable shifts of Barx1 expression domains along the proximo-distal axis and, consequently, in the formation of repositioned joints. Our data suggest that during early limb bud development in chick, Meis1 and Hoxa11 expression domains are overlapping, whereas the Barx1 expression domain resides within the Hoxa11 expression domain. However, once the interzone is formed, the expression domains are refined and the Barx1 expression domain becomes congruent with the border of these two putative segment markers.

Simultaneous differentiation of articular and transient cartilage: WNT-BMP interplay and its therapeutic implication.

Limb skeleton forms through the process of endochondral ossification. This process of osteogenesis proceeds through an intermediate cartilage template and involves several stages of chondrocyte maturation and eventual bone formation. During the process of endochondral ossification, interplay between BMP and WNT signaling regulate simultaneous differentiation of articular and transient cartilage. In this review, we focus on the recent literature which explores the simultaneous differentiation of these two different types of cartilage. We discuss a new paradigm of developmental biology-inspired tissue engineering of bone and cartilage grafts and provide novel insight into treatment of osteoporosis.