Dysregulation of hedgehog signalling predisposes to synovial chondromatosis

Abstract

Synovial chondromatosis is a condition affecting joints in which metaplastic cartilage nodules arise from the synovium, causing pain, joint dysfunction, and ultimately joint destruction. Because dysregulation of hedgehog signalling is a feature of several benign cartilaginous tumours, expression of the hedgehog target genes PTC1 and GLI1 was examined in this study in samples from human synovial chondromatosis. Significantly higher expression levels were found in synovial chondromatosis than in the synovium, from which it arises. To determine if hedgehog-mediated transcription predisposes to synovial chondromatosis, the extra-toes mutant mouse, which harbours a heterozygous mutation in the hedgehog transcriptional repressor, Gli3, resulting in decreased expression of Gli3 protein, was studied. The extra-toes mutant mouse has a phenotype consistent with overactive hedgehog signalling, suggesting that Gli3 acts as a transcriptional repressor of limb development. Eighty-five per cent of Gli3 mutant mice developed synovial chondromatosis at 18 months of age, compared with 30% of wild-type littermates (p < 0.05). Three of the ten Gli3 mutant mice treated with triparanol, which blocks hedgehog signalling upstream of the Gli transcription factors, developed synovial chondromatosis, compared with eight of ten control mice. These data demonstrate that hedgehog signalling plays an important role in the development of synovial chondromatosis and suggest that blockade of hedgehog signalling may be a potential treatment for this disorder.

PATCHED-ONE or SMOOTHENED Gene Mutations Are Infrequent in Chondrosarcoma

“…In fact, the only sample of the benign condition synovial chondromatosis, which was examined, harbored the same SMO variant as a dedifferentiated chondrosarcoma. Although we did not investigate the functional aspects of the PTCH-1 polymorphisms or R168H SMO variant as part of this study, these alterations may still affect the hedgehog signaling pathway, which we previously found was overexpressed in a variety of cartilage neoplasia [8,9,32,37].…”

“…We previously identified the PTHR1 R150C mutation of the parathyroid hormone-related peptide (PTHrP) receptor gene (PTHR1) in two patients with enchondromatosis, which resulted in overactivation of the hedgehog pathway [8]. We subsequently reported evidence of increased hedgehog signaling in a variety of benign as well as malignant cartilage tumors, suggesting dysregulation of this pathway is a critical event in cartilage neoplasia [9,32].…”

Wnt9a signaling is required for joint integrity and regulation ofIhhduring chondrogenesis

“…The etiology of this disease is largely unknown. However, deregulation of hedgehog signaling has recently been implicated in disease predisposition (Hopyan et al, 2005). It originates from chondroid metaplasia of connective tissue of the synovial membrane, causing pain, joint dysfunction and ultimately joint destruction.…”

Don't hedge your bets: Hedgehog signaling as a central mediator of endochondral bone development and cartilage diseases

“…In human synovial chondromatoses, the downstream Hh signaling target genes GLI1 and PTCH1 are expressed at higher levels as compared to normal synovium. 45 Furthermore, disturbing the negative regulation of Hh signaling through deletion of one allele of GLI3 results in an increased incidence of synovial chondromatoses in mice. 45 Therefore, as with enchondromas, the pathogenesis of synovial chondromatoses also appears to be related to increases in Hh signaling.…”