Skeletal phenotype of mice lacking HIP/RPL29, a component of the large ribosomal subunit

Abstract

Ribosomal proteins (RPs) play important regulatory functions in the ribosome and modulate protein synthetic rates in response to external cues. Disruption of the heparan sulfate interacting protein/Rpl29 (Hip/Rpl29) gene caused a global growth defect in homozygous null mutants, resulting in a short stature phenotype that is apparent from prenatal life through adulthood. In primary mouse embryonic fibroblasts, the absence of HIP/RPL29 is accompanied by a reduction in proliferation and protein synthesis, and a decrease in the steady state levels of core ribosomal components. Interestingly, the proliferation index of HIP/RPL29 null chondrocytes remains unaffected in developing growth plates suggesting that the skeletal growth defect might rather be a consequence of a deficiency in bone matrix synthesis. To investigate the postnatal effects of HIP/RPL29 absence on adult bone structure, I compared the wet weight of individual long bones (femur and tibia) in null mutants and control mice. I found that the average bone weight is approximately 30% lower in null animals when compared to corresponding bones in controls. I also evaluated the cortical and trabecular bone morphology differences between HIP/RPL29 null and control animals using standard histology and micro-computed tomography (micro-CT). We found that HIP/RPL29 null femoral diaphyses exhibit a significant decrease in bone marrow (40%) and cortical (15%) areas. In addition, a significant 30% decrease in the polar moment of inertia in HIP/RPL29-deficient bones was observed. On the other hand, no significant differences were detected in the trabecular microstructure of the distal femur in null mice when compared to controls. Altogether, these data show that the amount of total bone tissue is decreased in mice lacking a regulatory component of the ribosome, supporting the idea that high volume protein synthesis is essential for bone matrix production during periods of rapid bone growth, predominantly during development. Stimulation of this pathway might provide novel means of accelerating bone and connective tissue regrowth during wound healing.