Celecoxib treatment of fibrous dysplasia (FD) in a human FD cell line and FD-like lesions in mice with protein kinase A (PKA) defects

Abstract

Osteochondromyxomas (OMX) in the context of Carney complex (CNC) and fibrous dysplasia (FD)-like lesions (FDLL) in mice, as well as isolated myxomas in humans may be caused by inactivation of PRKAR1A, the gene coding for the type 1a regulatory subunit (R1α) of cAMP–dependent protein kinase (PKA). OMXs and FDLL in mice lacking Prkar1a grow from abnormal proliferation of adult bone stromal cells (aBSCs). Prkar1a and Prkaca (coding for Cα) haploinsufficiency lead to COX2 activation and prostaglandin E2 (PGE2) production that, in turn, activates proliferation of aBSCs. Celecoxib is a cyclooxygenase-2 (COX2) inhibitor. We hypothesized that COX-2 inhibition may have an effect in FD and FDLL. In vitro treatment of a human cell line prepared from a FD patient with Celecoxib resulted in decreased PGE2 and cell proliferation. Treatment of mice haploinsufficient for R1α and Cα with 1,500 mg/kg Celecoxib led to decreased PGE2 and proliferation and increased apoptosis, with a corresponding gene expression profile, resulting in dramatic reduction of tumor growth. Furthermore, the treatment improved the organization of cortical bone that was adjacent to the tumor. We conclude that, in vitro and in vivo, Celecoxib had an inhibitory effect on FD cell proliferation and in mouse FDLL structure, respectively. We speculate that COX-2 inhibitors offer an attractive alternative to current treatments for benign tumors such as OMX and FD that, apart from tumor suppression, may mechanically stabilize affected bones.

IL-33 facilitates proliferation of colorectal cancer dependent on COX2/PGE2

“…It is well known that COX2, a key enzyme for PGE 2 synthesis, can be effectively inhibited by the FDA-approved drug celecoxib [ 57 , 58 ]. We have circumspectly selected appropriate dosages of SC-560 and celecoxib to inhibit COX1 and COX2, respectively, as their selectivity depends on the concentrations [ 59 – 61 ].…”

HDAC8, A Potential Therapeutic Target, Regulates Proliferation and Differentiation of Bone Marrow Stromal Cells in Fibrous Dysplasia

“…However, its application in clinical practice requires further study to clarify the value of HDAC8 as a novel therapeutic target in FD. This issue may be addressed by constructing a better animal model of FD and by examining the drug metabolism and pharmacokinetics of HDAC8‐specific inhibitors. Recent research appeared that a conditional tetracycline‐inducible animal model expressing the Gα s R201C in the skeletal stem cell linage was established and represented FD‐like bone lesions .…”

Bone tissue and mineral metabolism in hereditary endocrine tumors: clinical manifestations and genetic bases

“…PRKAR1A haploinsufficiency induces cyclooxygenase-2 (COX2) activation and prostaglandin E2 (PGE2) overproduction, associated with abnormal proliferation of bone stromal cells of CNC osteochondromyxomas. Administration of celecoxib, a COX2 inhibitor, in mice with PKA defects decreased PGE2 level and reduced the proliferation of bone stromal cells, resulting in important reduction of osteochondromyxoma growth and better organization of the cortical bone adjacent to the mass [67]. This pivotal study suggests the possibility to use this drug for the treatment of bone affections in CNC.…”

“…NF1 is characterized by a pathological triad: 1) multiple benign tumors of the nerves (neurofibromas); 2) pigmented skin lesions (café-au-lait spots and fibrous tumors); and 3) iris hamartomas (Lisch nodules) [67,68]. Affected individuals have greater susceptibility to the development of benign and malignant tumors, such as neurofibromas, neurofibrosarcomas, gliomas, PHEO, myeloid leukemia, pancreatic and duodenal NETs (especially somatostatinomas) [77,79]; (Table 1).…”