Development of severe skeletal defects in induced SHP-2-deficient adult mice: a model of skeletal malformation in humans with SHP-2 mutations

Abstract

SUMMARYSHP-2 (encoded by PTPN11) is a ubiquitously expressed protein tyrosine phosphatase required for signal transduction by multiple different cell surface receptors. Humans with germline SHP-2 mutations develop Noonan syndrome or LEOPARD syndrome, which are characterized by cardiovascular, neurological and skeletal abnormalities. To study how SHP-2 regulates tissue homeostasis in normal adults, we used a conditional SHP-2 mouse mutant in which loss of expression of SHP-2 was induced in multiple tissues in response to drug administration. Induced deletion of SHP-2 resulted in impaired hematopoiesis, weight loss and lethality. Most strikingly, induced SHP-2-deficient mice developed severe skeletal abnormalities, including kyphoses and scolioses of the spine. Skeletal malformations were associated with alterations in cartilage and a marked increase in trabecular bone mass. Osteoclasts were essentially absent from the bones of SHP-2-deficient mice, thus accounting for the osteopetrotic phenotype. Studies in vitro revealed that osteoclastogenesis that was stimulated by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa B ligand (RANKL) was defective in SHP-2-deficient mice. At least in part, this was explained by a requirement for SHP-2 in M-CSF-induced activation of the pro-survival protein kinase AKT in hematopoietic precursor cells. These findings illustrate an essential role for SHP-2 in skeletal growth and remodeling in adults, and reveal some of the cellular and molecular mechanisms involved. The model is predicted to be of further use in understanding how SHP-2 regulates skeletal morphogenesis, which could lead to the development of novel therapies for the treatment of skeletal malformations in human patients with SHP-2 mutations.

Noonan syndrome-causing SHP2 mutants inhibit insulin-like growth factor 1 release via growth hormone-induced ERK hyperactivation, which contributes to short stature

“…Finally, our data do not exclude that other processes, independent of the GH/ IGF-1 axis, could be impaired in NS mice and result in growth retardation. Indeed, skeletal and growth abnormalities have been reported in inducible and neuronal-specific SHP2 knockout models (27,28). Further studies will be necessary to elucidate the part of those different mechanisms in NS-associated short stature.…”

TLT-1s, Alternative Transcripts of Triggering Receptor Expressed on Myeloid Cell-like Transcript-1 (TLT-1), Inhibits the Triggering Receptor Expressed on Myeloid Cell-2 (TREM-2)-mediated Signaling Pathway during Osteoclastogenesis

“…On the other hand, ITIMbearing adaptor molecules are known to inhibit ITAM signaling via a recruitment of phosphatases such as SHP-1, SHP-2, and SHIP proteins. SHP-1 and SHIP-1 knock-out mice are reported to exhibit severe osteoporosis because of a dramatically increased number of osteoclasts (21,22). Because TLT-1s lacks the extracellular Ig domain compared with full-length TLT-1, we hypothesized that TLT-1s acts as a genuine adaptor molecule in a similar fashion with DAP12 and FcR␥ that are also deficient in the extracellular domain.…”

Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

“…In the case of NS, scoliosis and other spinal deformities are frequently encountered [49,50] and it was recently reported that NS children may have decreased bone mineralization [51], even though this study was performed on a limited number of patients. This hypothesis is also based on a recent report showing that PTPN11 disruption causes severe skeletal defects in mice [52]. Nonetheless the validity of this hypothesis has not been tested yet.…”