From Stem to Sternum: The Role of Shp2 in the Skeleton

Jensen, Nathaniel R.; Kelly, Ryan R.; Kelly, Kirsten D.; Khoo, Stephanie K.; Sidles, Sara J.; LaRue, Amanda C.

doi:10.1007/s00223-022-01042-3

Cited by 2 publications

(4 citation statements)

References 148 publications

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“…Bone metabolic disease in NS has been supported to be partly primary resulting from an imbalance between osteoclast and osteoblast activity due to RAS/ERK hyperactivation, as discussed below ( 33 , 37 , 71 ). Notably, recent results from experiments in transgenic NS mice revealed an essential role of SHP2 in promoting osteoblastic differentiation and suppressing osteoclastogenesis ( 74 , 75 ). Moreover, BMD was shown to correlate with decreased muscle mass and low IGF-1 levels ( 37 ), while low gonadal steroids also supported to contribute to the final bone phenotype ( 37 , 48 , 68 , 76 ).…”

Section: Musculoskeletal Features and Biochemical Bone Profilementioning

confidence: 99%

“…In a subsequent study, the lack of SHP2 from hypertrophic chondrocytes showed a significantly decreased number of osteoblasts in the cancellous bone and repressed osteogenic gene expression suggesting a potential role for SHP2 in the regulation of hypertrophic chondrocyte transdifferentiation ( 115 ). The significantly diverse phenotypes of the mice lacking SHP2 in proliferating and hypertrophic chondrocytes indicate a developmental stage-specific role for SHP2 in chondrogenesis and bone mineral homeostasis ( 114 ), reviewed in ( 75 ).…”

Section: Ras/mapk Cascade and Bone Defectsmentioning

confidence: 99%

“…In this direction, genetic or pharmacologic inhibition of SHP2 has emerged as a critical node for therapeutic applications. Although various SHP2 competitive inhibitors have been reported, only a few allosteric SHP2 inhibitors have been developed and progressed in clinical trials [for detailed review see ( 75 )]. These allosteric SHP2 inhibitors have been extensively studied in cancer ( 123 ) and its introduction to other human genetic diseases and musculoskeletal pathologies is currently under investigation ( 124 , 125 ).…”

Section: Ras/mapk Cascade and Bone Defectsmentioning

confidence: 99%

“…A recent review in multiple Hras CS models highlighted the importance of bioenergetics and mitochondrial proteostasis in heart and skeletal muscles and proposed that CS patients may benefit from regimen with mitochondrial modulators ( 130 ). Certainly, high quality clinical studies are warranted to shed light on various aspects and limitations which accompany the novel targeted therapies ( 23 , 75 ).…”

Section: Ras/mapk Cascade and Bone Defectsmentioning

confidence: 99%

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Skeletal defects and bone metabolism in Noonan, Costello and cardio-facio-cutaneous syndromes

Papadopoulou,

Bountouvi

2023

Front. Endocrinol.

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Noonan, Costello and Cardio-facio-cutaneous syndromes belong to a group of disorders named RASopathies due to their common pathogenetic origin that lies on the Ras/MAPK signaling pathway. Genetics has eased, at least in part, the distinction of these entities as they are presented with overlapping clinical features which, sometimes, become more pronounced with age. Distinctive face, cardiac and skeletal defects are among the primary abnormalities seen in these patients. Skeletal dysmorphisms range from mild to severe and may include anterior chest wall anomalies, scoliosis, kyphosis, short stature, hand anomalies, muscle weakness, osteopenia or/and osteoporosis. Patients usually have increased serum concentrations of bone resorption markers, while markers of bone formation are within normal range. The causative molecular defects encompass the members of the Ras/MAPK/ERK pathway and the adjacent cascades, important for the maintenance of normal bone homeostasis. It has been suggested that modulation of the expression of specific molecules involved in the processes of bone remodeling may affect the osteogenic fate decision, potentially, bringing out new pharmaceutical targets. Currently, the laboratory imprint of bone metabolism on the clinical picture of the affected individuals is not clear, maybe due to the rarity of these syndromes, the small number of the recruited patients and the methods used for the description of their clinical and biochemical profiles.

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