In humans, gain-of-function and loss-of-function mutations of the SHP-2 protein tyrosine phosphatase (PTP) cause Noonan syndrome (NS) and LEOPARD syndrome (LS), respectively. Noonan syndrome is relatively common, affecting between 1 in 1000 and 1 in 5000 live births, whereas LEOPARD syndrome is much rarer. Both are autosomal dominant diseases with variable penetrance. The syndromes have several overlapping features, including skeletal abnormalities such as growth retardation and chest malformations; in NS, sufferers often have additional elbow and hand malformations and spinal curvature. How mutations in SHP-2 lead to skeletal malformation is unknown.
The development of an inducible systemic SHP-2-deficient mouse model would enable greater understanding of the role of SHP-2 in skeletal growth and remodeling. Here, the authors report that induced broad deletion of the ptpn11 gene (which encodes SHP-2) in adult mice results in multiple tissue abnormalities. The most prominent of these is severe curvature of the spine, causing both scoliosis (side-to-side curvature) and kyphosis (hunched back). These skeletal malformations are associated with osteopetrosis and cartilage alterations. A principal cause of the osteopetrosis in this model is defective osteoclastogenesis (differentiation of the cells that resorb bone). In SHP-2-deficient osteoclast precursor cells, the growth factor macrophage colonystimulating factor (M-CSF) cannot induce activation of AKT protein kinase, which is essential for osteoclast precursor survival and differentiation.
Implications and future directions
Loss of function of SHP-2 in mice causes skeletal abnormalities in part by inhibiting bone remodeling, and it is likely that the same process is disrupted in humans with LS. The model described here will be useful for identifying and dissecting the signaling pathways that are controlled by SHP-2 during skeletal morphogenesis, and might also yield new information about mechanisms of bone regulation in general. Such studies will aid the rational design of therapeutics for treatment of skeletal disorders in humans with inherited SHP-2 mutations.
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