Targeted Ptpn11 deletion in mice reveals the essential role of SHP2 in osteoblast differentiation and skeletal homeostasis

The maturation and function of osteoblasts(OBs)rely heavily on the reversible phosphorylation of signaling proteins.To date,most of the work in OBs has focused on phosphorylation by tyrosyl kinases,but little has been revealed about dephosphorylation by protein tyrosine phosphatases(PTPases).SHP2(encoded by PTPN11)is a ubiquitously expressed PTPase.PTPN11 mutations are associated with both bone and cartilage manifestations in patients with Noonan syndrome(NS)and metachondromatosis(MC),although the underlying mechanisms remain elusive.Here,we report that SHP2 deletion in bone gamma-carboxyglutamate protein-expressing(Bglap+)bone cells leads to massive osteopenia in both trabecular and cortical bones due to the failure of bone cell maturation and enhanced osteoclast activity,and its deletion in Bglap+chondrocytes results in the onset of enchondroma and osteochondroma in aged mice with increased tubular bone length.Mechanistically,SHP2 was found to be required for osteoblastic differentiation by promoting RUNX2/OSTERIX signaling and for the suppression of osteoclastogenesis by inhibiting STAT3-mediated RANKL production by osteoblasts and osteocytes.These findings are likely to explain the compromised skeletal system in NS and MC patients and to inform the development of novel therapeutics to combat skeletal disorders.

Protein tyrosine phosphatases in skeletal development and diseases

Skeletal development and homeostasis in mammals are modulated by finely coordinated processes of migration, proliferation,differentiation, and death of skeletogenic cells originating from the mesoderm and neural crest. Numerous molecular mechanisms are involved in these regulatory processes, one of which is protein posttranslational modifications, particularly protein tyrosine phosphorylation(PYP). PYP occurs mainly through the action of protein tyrosine kinases(PTKs), modifying protein enzymatic activity, changing its cellular localization, and aiding in the assembly or disassembly of protein signaling complexes. Under physiological conditions, PYP is balanced by the coordinated action of PTKs and protein tyrosine phosphatases(PTPs).Dysregulation of PYP can cause genetic, metabolic, developmental, and oncogenic skeletal diseases. Although PYP is a reversible biochemical process, in contrast to PTKs, little is known about how this equilibrium is modulated by PTPs in the skeletal system.Whole-genome sequencing has revealed a large and diverse superfamily of PTP genes(over 100 members) in humans, which can be further divided into cysteine(Cys)-, aspartic acid(Asp)-, and histidine(His)-based PTPs. Here, we review current knowledge about the functions and regulatory mechanisms of 28 PTPs involved in skeletal development and diseases;27 of them belong to class Ⅰ and Ⅱ Cys-based PTPs, and the other is an Asp-based PTP. Recent progress in analyzing animal models that harbor various mutations in these PTPs and future research directions are also discussed. Our literature review indicates that PTPs are as crucial as PTKs in supporting skeletal development and homeostasis.

Gastric cancer with soft tissue metastasis of the abdominal wall:a case report

Abdominal wall metastasis of gastric cancer(GC)is a very rare occurrence in the clinic setting.We recently diagnosed and treated a patient with abdominal wall metastasis of GC and we hope to provide some helpful guidance on the clinical diagnosis and treatment of this disease.A 49-year-old male patient with GC was admitted to our hospital(Dalian Municipal Central Hospital,Dalian,China)complaining of left upper abdominal wall mass.Physical examination and regular laboratory blood tests showed no obvious abnormalities.Ultrasound and CT of the abdomen showed a subcutaneous solid mass in the abdominal wall.Radical gastrectomy was performed on February 27,2019,six months after it was first noticed by the patient.Pathological examination and immunohistochemistry showed GC with abdominal metastasis.Postoperative radiotherapy or chemotherapy was not pursued after the second operation and no recurrence or metastasis has been noted so far.GC with abdominal metastasis is very rare and can be easily missed or misdiagnosed.For metastasis to a single site in the abdominal wall,surgical resection,which is recommended,may improve patient outcomes.

Unplanned surgery of congenital scoliosis

To the Editor:There is a high probability of requiring unplanned surgery for congenital scoliosis(CS),but very few publications have reported the proportion of unplanned surgeries,the causes of those unplanned surgeries,and the prevalence of each cause.This study aimed to provide more information regarding the above.We reviewed the electronic medical records of patients with CS that underwent unplanned surgeries at our hospital from 2009 to 2018.By searching the database of West China Hospital,we found 317 CS cases.Of these,33 cases underwent unplanned surgeries,of which five had their primary surgeries at outside hospitals.The unplanned surgery rate in our case series was 9.0%(28/312).In our case series,the most common cause of unplanned surgery for patients with CS was progressive deformity(49%,16/33),followed by implant-related complications(36%,12/33),wound-related complications(12%,4/33),and surgical error-related complications(cerebrospinal fluid[CSF]leak,3%,1/33).The most common reason for unplanned surgery in CS was progressive spinal deformity or imbalance,which accounted for 49%(16/33)of the unplanned surgeries.