Bmp-4 Requires the Presence of the Digits to Initiate Programmed Cell Death in Limb Interdigital Tissues

Abstract

The effects of Bmp-4 on interdigital cell death were investigated in the mouse. Affi-Gel beads, loaded with recombinant Bmp-4 protein, were transplanted into the interdigital tissues of day 12.5 hindlimb, ex utero. It was established that Bmp-4 could induce precocious interdigital cell death. Using in situ hybridization, the expression patterns of bmp-4 and alk-6 receptor were established. Both genes were found coexpressed in the interdigital region of 12.5- and 13. 5-day hindlimbs. This suggests that Bmp-4 may act in an autocrine fashion. We have also studied the effects of Bmp-4 on 12.5-day interdigital tissue cultures. In all specimens examined, the interdigital tissues produced cartilage instead of participating in cell death. The addition of exogenous Bmp-4 to the interdigital cultures did not induce apoptosis but instead enhanced chondrogenesis. The discrepancy between the effects of Bmp-4 in vitro and ex utero was attributed to the presence of digits. When a flanking digit was left attached to the interdigital tissues, in vitro, Bmp-4 promoted apoptosis instead of chondrogenesis. In sum, the results suggest that Bmp-4 is a multifunctional protein and its effect on the interdigital tissues is dependent on the modulating influence of the digits.

Overexpression of bone morphogenetic protein-6 (BMP-6) in murine epidermis suppresses skin tumor formation by induction of apoptosis and downregulation of fos/jun family members

“…TGF-b1 is known to induce apoptosis in various cell-types (Guo and Kyprianou, 1999;Motyl et al, 1998;Teramoto et al, 1998) and a requirement of BMP-2, -4 and -7 to initiate cell death in limb interdigital tissue is well established (Merino et al, 1998;Tang et al, 2000;Yokouchi et al, 1996). Our ®ndings show that epidermal apoptotic frequencies in BMP-6 transgenic mice are elevated both in unchallenged skin and during tumor promotion suggesting that BMP-6 can induce apoptosis in keratinocytes.…”

A Comprehensive Analysis of the Dual Roles of BMPs in Regulating Adipogenic and Osteogenic Differentiation of Mesenchymal Progenitor Cells

“…We have demonstrated that several BMPs are potent inducers of osteogenesis of MSCs [27][28][29][30][31][32], and that osteogenic BMPs (e.g., BMP-2, BMP-6, and BMP-9) regulate a distinct set of downstream targets that may play a role in regulating BMP-induced osteoblast differentiation [27,[30][31][32][33]. BMP-2, BMP-4, and BMP-7, in coordination with other signaling molecules or supplementary cofactors, have been shown to promote preadipocyte differentiation [34][35][36][37][38][39][40][41][42][43][44][45][46]. However, the biological effects of BMPs on multiple lineage commitment and terminal differentiation of MSCs have not comprehensively analyzed.…”

The homeobox transcription factor Barx2 regulates chondrogenesis during limb development

“…In developing limbs, BMPs and BMP-related molecules, such as the growth and differentiation factors (GDFs), have been implicated in the establishment of limb axes, chondrogenesis, osteogenesis and tissue patterning by apoptosis (Hoffmann and Gross, 2001;Macias et al, 1997;Niswander, 2002;Pizette et al, 2001;Tang et al, 2000;Yi et al, 2000). BMPs induce the expression of specific markers of chondrogenesis (Enomoto-Iwamoto et al, 1998;Shea et al, 2003;Tsumaki et al, 2002) via a transcriptional cascade that often involves other regulators such as Sox and homeobox proteins (Baur et al, 2000;Boulet and Capecchi, 2004;Zhang et al, 2000).…”