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Methods for diagnosing osteoarthritis

a technology of osteoarthritis and prognosis, applied in the field of osteoarthritis prognosis, can solve the problems of incomplete knowledge of the biology of oa, the functional importance of these susceptibility loci has not yet been confirmed,

Inactive Publication Date: 2015-06-04
VALORISATION HSJ LLP
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent is about a new method to diagnose and predict who will develop osteoarthritis. The method involves detecting a specific mutation in the pitx1 gene that causes the accumulation and retention of proteins in cell nuclear. The patent also describes a kit that contains the necessary reagents to detect this mutation. The technical effects of this invention are to provide a more accurate and effective way to diagnose and prevent osteoarthritis.

Problems solved by technology

Moreover, the functional importance of these susceptibility loci has yet to be confirmed and illustrates our incomplete knowledge of the biology of OA.

Method used

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  • Methods for diagnosing osteoarthritis
  • Methods for diagnosing osteoarthritis
  • Methods for diagnosing osteoarthritis

Examples

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example 1

[0138]Comparison of Pitx1 Expression in Articular Chondrocytes of OA Subjects with that of in Articular Chondrocytes Matched Controls

[0139]To determine whether pitx1 plays a role in the genetic control of OA onset, an expression analysis of pitx1 gene using RNA prepared from articular chondrocyte cultures derived from knee cartilage of OA patients (n=7) and age- and gender-matched control subjects (n=4) was performed. Pitx1 expression was detected only in articular chondrocytes derived from matched controls, while in OA articular chondrocytes, Pitx1 expression was abrogated or barely detectable by RT-PCR (FIG. 2A). Analysis of Pitx1 protein levels and distribution in human knee joint sections showed Pitx1 proteins only in control cartilages (n=8), while Pitx1 proteins were hardly detected in OA cartilage sections (n=8) (FIGS. 2B-D).

example 2

Identification of Pitx1 Promoter Mutation

[0140]To examine the mechanisms turning off pitx1 gene expression in OA patients, the 5′ regulatory region of human pitx1 gene was examined for specific mutations leading to a progressive loss of Pitx1 expression during adulthood. Sequencing analysis of genomic DNA obtained from OA, rheumatoid arthritis (RA) and matched control subjects revealed, along a 10 kb promoter region of human pitx1 gene, a single homozygous mutation (−3727 C→T) (position corresponds to distance from transcription point) affecting only OA patients (11 / 43) with a high frequency (25%) while none of the RA patients (0 / 29) and matched control subjects (0 / 11) had the homozygous mutation. The specificity, the positive predictive values and negative predictive values of the mutation were calculated for each group as reported in Table 4 below. A statistically significant association between the mutation and diagnosis was calculated (two-tailed test) by comparing OA versus RA ...

example 3

Determination of Functional Consequences of Mutation in the E2F-Like Site on Complex Binding

[0142]To determine the functional consequences of the homozygous mutation found in OA patients, it was investigated whether E2Fs were able to bind this E2F-like site using nuclear extracts prepared with OA articular chondrocytes as described above. EMSA analysis using both radiolabeled E2F-like sites (wild-type FIG. 4A versus mutant FIG. 4B) showed no supershift of the bound complex with any antibodies against E2Fs, or their dimerization partners DP-1 or DP-2 (E2F2, E2F8 and DP2 data not shown). The Sp1 and Sp3 transcription factors were also analysed since they bind GC-rich regions such as the E2F-like site found in the human Pitx1 promoter. Unfortunately, there was no supershift with either anti-Sp1 or anti-Sp3 antibodies. Addition of BCoR antibodies generated the binding of an additional lower complex bound in presence of either probes although the binding was increased with the mutant one...

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Abstract

A method of predicting the risk of developing osteoarthritis (OA) comprising: (a) measuring the nuclear cellular level of prohibitin (PHB-1) in nucleated cells present in a blood sample from a subject having or suspected of having OA; and (b) comparing said nuclear cellular level to that corresponding to a control sample; and (c) identifying the subject as being at risk of developing OA when the nuclear cellular level of said PHB-1 in said blood sample is higher than in the control sample.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 12 / 447,152, which is a National Entry Application of PCT Application Serial No. PCT / CA2007 / 001901 filed on Oct. 25, 2007 and published in English under PCT Article 21(2), which itself claims priority on U.S. Provisional Application Ser. No. 60 / 854,077 filed on 25 Oct. 2006. All documents above are incorporated herein in their entirety by reference.FIELD OF THE INVENTION[0002]The present invention relates to methods of prognosing osteoarthritis, methods of selecting compounds and kits therefore.REFERENCE TO SEQUENCE LISTING[0003]Pursuant to 37 C.F.R. 1.821(c), a sequence listing is submitted herewith as an ASCII compliant text file named 12810—230_ST25, that was created on Dec. 11, 2014 and having a size of 34 kilobytes. The content of the aforementioned file is hereby incorporated by reference in its entirety.BACKGROUND OF THE INVENTION[0004]The etiology of (OA), the m...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): G01N33/68
CPCG01N33/6893G01N2333/47G01N2800/50G01N2800/105C07K14/4703C12Q1/6883C12Q2600/158C12Q2600/136C12Q2600/156G01N2333/4704G01N2333/4706
Inventor MOREAU, ALAIN
Owner VALORISATION HSJ LLP
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