Article Text

  1. J. Gordon1,
  2. K. N. Retting1,
  3. K M. Lyons2
  1. 1UCLA David Geffen School of Medicine, Los Angeles, CA; Department of Cell and Developmental Biology, UCLA, Los Angeles, CA
  2. 2Cell and Developmental Biology, Department of Orthopedic Surgery, Department of Biological Chemistry, UCLA, Los Angeles, CA


Bone morphogenetic proteins (BMPs), members of the TGF-beta superfamily, are involved in cellular differentiation and a number of pathologic conditions. Mice deficient in BMP receptors Bmpr1a and Bmpr1b present phenotypically with severe chondrodysplasia. BMPs signal through Smad proteins, which play several essential roles during cellular development. It is known that signaling proteins Smad 1, 5, and 8 are the direct targets for BMPR1A and BMPR1B. Smad 1, 5, and 8 are phosphorylated by BMPRs, allowing interactions with Smad 4 and relocation to the nucleus, thus altering gene transcription and cellular maturation. Despite their importance, the function and interaction patterns of Smad proteins remain unclear. It is hypothesized that inter-Smad regulation and functional overlap exists between Smads 1, 5, and 8. We tested this hypothesis through the generation of mice lacking Smad1 or Smad8 singly or in combination using Cre-loxP technology and a floxed allele of Smad1. Genotypic and phenotypic analyses were used to examine Smad 1, 5, and 8 interactions. A PCR multiplex strategy was designed to genotype potential Smad mutants. After identification of informative litters, comparisons were made using histologic, skeletal preparation, and immunofluorescent staining techniques. In Smad1 and Smad8 mutants, skeletal preparations revealed essentially unaffected gross patterning. This phenotype suggests that either there is extensive functional redundancy, non-Smad signaling, based on comparison with Bmpr1a/Bmpr1b knockout phenotypes. Histologic slides revealed subtle disorganization within the growth plates of Smad1CKO; Smad8 +/{1338} (CKO = cartilage-specific knockout) mice that was not apparent in Smad1CKO or Smad8−/− mice, demonstrating a role for these Smads in the growth plate, and functional redundancy. Immunofluorescence highlighted comparable levels of phospho-Smad 1, 5, and 8 staining in Smad1CKO; Smad8+/− mice and WT littermates. This suggests compensatory up-regulation of Smad 5/8 proteins in the absence of Smad 1. Taken together, our results support roles for Smads in transducing BMP signaling in the growth plate and suggest a high degree of functional redundancy among the members of the Smad 1, 5, 8 subgroup.

Statistics from

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.