Multicentric carpotarsal osteolysis is caused by mutations clustering in the amino-terminal transcriptional activation domain of MAFB

Multicentric carpotarsal osteolysis (MCTO) is a rare skeletal dysplasia characterized by aggressive osteolysis, particularly affecting the carpal and tarsal bones, and is frequently associated with progressive renal failure. Using exome capture and next-generation sequencing in five unrelated simplex cases of MCTO, we identified previously unreported missense mutations clustering within a 51 base pair region of the single exon of MAFB, validated by Sanger sequencing. A further six unrelated simplex cases with MCTO were also heterozygous for previously unreported mutations within this same region, as were affected members of two families with autosomal-dominant MCTO. MAFB encodes a transcription factor that negatively regulates RANKL-induced osteoclastogenesis and is essential for normal renal development. Identification of this gene paves the way for development of novel therapeutic approaches for this crippling disease and provides insight into normal bone and kidney development.

Erratum: Multicentric carpotarsal osteolysis is caused by mutations clustering in the amino-terminal transcriptional activation domain of MAFB

(The American Journal of Human Genetics, 90, 494–501; March 9, 2012) In the published version of this article, the amino acid alteration caused by c.161C>T should have been notated as p.Ser54Leu and not p.Pro54Leu. The wild-type amino acid is incorrectly notated in the main text, in Table 2, and in Figure 4. The authors regret this error. Additionally, The Journal regrets that this erratum, originally requested in 2012, was not published in a timely fashion.

CCR2 Deficiency Results in Increased Osteolysis in Experimental Periapical Lesions in Mice

Introduction: Periapical lesions are chronic inflammatory disorders of periradicular tissues caused by etiologic agents of endodontic origin. The inflammatory chemokines are thought to be involved in the latter observed osteolysis. With a murine model of experimental periapical lesion, the objective of this study was to evaluate the role of the chemokine receptor CCR2 in the lesion progression, osteoclast differentiation and activation, and expression of inflammatory osteolysis-related mediators. Methods: For lesion induction, right mandibular first molars were opened surgically with a (1)/(4) carbine bur, and 4 bacterial strains were inoculated in the exposed dental pulp; left mandibular first molars were used as controls. Animals were killed at 3, 7, 14, and 21 days after surgeries to evaluate the kinetics of lesion development. Results: CCR2 KO mice showed wider lesions than WT mice. CCR2 KO mice also expressed higher levels of the osteoclastogenic and osteolytic factors, receptor activator of nuclear factor kappa B ligand (RANKL) and cathepsin K, of the proinflammatory cytokine tumor necrosis factor alpha, and of the neutrophil migration related chemokine, KC. Conclusions: These results suggest that CCR2 is important in host protection to periapical osteolysis. (J Endod 2010;36:244-250)

Multicentric Carpotarsal Osteolysis Is Caused by Mutations Clustering in the Amino-Terminal Transcriptional Activation Domain of MAFB

Multicentric carpotarsal osteolysis (MCTO) is a rare skeletal dysplasia characterized by aggressive osteolysis, particularly affecting the carpal and tarsal bones, and is frequently associated with progressive renal failure. Using exome capture and next-generation sequencing in five unrelated simplex cases of MCTO, we identified previously unreported missense mutations clustering within a 51 base pair region of the single exon of MAFB, validated by Sanger sequencing. A further six unrelated simplex cases with MCTO were also heterozygous for previously unreported mutations within this same region, as were affected members of two families with autosomal-dominant MCTO. MAFB encodes a transcription factor that negatively regulates RANKL-induced osteoclastogenesis and is essential for normal renal development. Identification of this gene paves the way for development of novel therapeutic approaches for this crippling disease and provides insight into normal bone and kidney development.

Is there a need for routine follow-up after primary total hip arthroplasty?

Background: The objective of routine outpatient assessment of well functioning patients after primary total hip arthroplasty (THA) is to detect asymptomatic failure of prostheses to guide recommendations for early intervention. We have observed that the revision of THAs in asymptomatic patients is highly uncommon. We therefore question the need for routine follow-up of patients after THA. Methods: A prospective analysis of an orthopaedic database identified 158 patients who received 177 revision THAs over a 4 year period. A retrospective chart review was conducted. Patient demographics, primary and revision surgery parameters and follow-up information was recorded and cross referenced with AOA NJRR data. Results: 110 THAs in 104 patients (average age 70.4 (SD 9.8 years). There were 70 (63.6%) total, 13 (11.8%) femoral and 27 (24.5%) acetabular revisions. The indications for revision were aseptic loosening (70%), dislocation (8.2%), peri-prosthetic fracture (7.3%), osteolysis (6.4%) and infection (4.5%). Only 4 (3.6%) were asymptomatic revisions. A mean of 5.3 (SD 5.2 and 1.9 (SD 5.3 follow-up appointments were required before revision in patients with and without symptoms, respectively. The average time from the primary to revision surgery was 11.8 (SD 7.23) years. Conclusions: We conclude that patients with prostheses with excellent long term clinical results as validated by Joint Registries, routine follow-up of asymptomatic THA should be questioned and requires further investigation. Based on the work of this study, the current practice of routine follow-up of asymptomatic THA may be excessively costly and unnecessary and a less resource-intensive review method may be more appropriate.

Mineralized human primary osteoblast matrices as a model system to analyse interactions of prostate cancer cells with the bone microenvironment

Prostate cancer metastasis is reliant on the reciprocal interactions between cancer cells and the bone niche/micro-environment. The production of suitable matrices to study metastasis, carcinogenesis and in particular prostate cancer/bone micro-environment interaction has been limited to specific protein matrices or matrix secreted by immortalised cell lines that may have undergone transformation processes altering signaling pathways and modifying gene or receptor expression. We hypothesize that matrices produced by primary human osteoblasts are a suitable means to develop an in vitro model system for bone metastasis research mimicking in vivo conditions. We have used a decellularized matrix secreted from primary human osteoblasts as a model for prostate cancer function in the bone micro-environment. We show that this collagen I rich matrix is of fibrillar appearance, highly mineralized, and contains proteins, such as osteocalcin, osteonectin and osteopontin, and growth factors characteristic of bone extracellular matrix (ECM). LNCaP and PC3 cells grown on this matrix, adhere strongly, proliferate, and express markers consistent with a loss of epithelial phenotype. Moreover, growth of these cells on the matrix is accompanied by the induction of genes associated with attachment, migration, increased invasive potential, Ca2+ signaling and osteolysis. In summary, we show that growth of prostate cancer cells on matrices produced by primary human osteoblasts mimics key features of prostate cancer bone metastases and thus is a suitable model system to study the tumor/bone micro-environment interaction in this disease.