Method of classifying human subjects having adolescent idiopathic scoliosis (ais) and method for screening for a compound useful in the treatment of ais and related syndromes causing spinal deformities

Abstract

A method of classifying a human subject having adolescent idiopathic scoliosis (AIS) comprising: providing a cell sample isolated from the subject; detecting an impairment in melatonin-signaling pathway in the sample in the presence and in the absence of a known melatonin-signaling pathway agonist, whereby the results of the detecting step enables the classification of the subject having AIS in one AIS subgroup; and a method of screening for a compound useful in the treatment of a disease characterized by a dysfunctional melatonin-signaling pathway, said method comprising the steps of contacting a candidate compound with at least one cell expressing at least one melatonin-signaling pathway impairment, wherein the candidate compound is selected if said melatonin-signaling pathway impairment is reduced in the presence of the candidate compound as compared to that in the absence thereof.

1 . A method of classifying a human subject having adolescent idiopathic scoliosis (AIS) comprising: providing a cell sample isolated from the subject; detecting an impairment in melatonin-signaling pathway in the sample in the presence and in the absence of a known melatonin-signaling pathway agonist, whereby the results of the detecting step enables the classification of the subject having AIS in one AIS subgroup. 
     
     
         2 . The method of  claim 1 , further comprising a step of selecting a treatment for the subject based on the results of the detecting step. 
     
     
         3 . The method of  claim 1 , wherein said known melatonin-signaling pathway agonist is melatonin. 
     
     
         4 . The method of  claim 1 , wherein said known melatonin-signaling pathway agonist is GTP. 
     
     
         5 . The method of  claim 1 , wherein the impairment is detected by an accumulation of cyclic adenosine 5′-monophosphate (cAMP) in the cell sample as compared to that in a control cell. 
     
     
         6 . The method of  claim 5 , wherein said accumulation of cAMP is induced by a known activator of adenylyl cyclase, and wherein the impairment is detected by an inhibition of said accumulation by a known melatonin-signaling pathway agonist that is detectably reduced in the cell sample as compared to that obtained in a control cell. 
     
     
         7 . The method of  claim 6 , wherein said known activator of adenylyl cyclase is forskolin. 
     
     
         8 . The method of  claim 1 , wherein the impairment is detected by an absence of proliferation of at least one of said cells in the presence of a known melatonin-signaling pathway agonist. 
     
     
         9 . The method of  claim 1 , wherein said cells are selected from the group consisting of osteoblasts, osteoclasts, lymphocytes, monocytes and myoblasts. 
     
     
         10 . The method of  claim 1 , wherein said cells are blood cells. 
     
     
         11 . The method of  claim 1 , wherein said cells are lymphocytes. 
     
     
         12 . A method of screening for a compound useful in the treatment of a disease characterized by a dysfunctional melatonin-signaling pathway, said method comprising the steps of
 contacting a candidate compound with at least one cell expressing at least one melatonin-signaling pathway impairment in the presence of a known melatonin-signaling pathway agonist,   wherein the candidate compound is selected if said melatonin-signaling pathway impairment is reduced in the presence of the candidate compound as compared to that in the absence thereof.   
     
     
         13 . The method of  claim 12 , wherein said disease characterized by a dysfunctional melatonin-signaling pathway is adolescent idiopathic scoliosis (AIS) or another disease involving spinal deformities. 
     
     
         14 . The method of  claim 12 , wherein said disease characterized by a dysfunctional melatonin-signaling pathway is adolescent idiopathic scoliosis (AIS). 
     
     
         15 . The method of  claim 12 , wherein said impairment is detected by an accumulation of cyclic adenosine 5′-monophosphate (cAMP) in said cell as compared to that in a control cell. 
     
     
         16 . The method of  claim 15 , further comprising the step of artificially inducing said accumulation of cyclic adenosine 5′-monophosphate (cAMP) by a known activator of adenylyl cyclase. 
     
     
         17 . The method of  claim 12 , wherein said known melatonin-signaling pathway agonist is melatonin or an analog thereof. 
     
     
         18 . The method of  claim 12 , wherein said known melatonin-signaling pathway agonist is GTP or an analog thereof. 
     
     
         19 . The method of  claim 16 , wherein said known activator of adenylyl cyclase is forskolin or an analog thereof. 
     
     
         20 . The method of  claim 12 , wherein said impairment is detected by an absence of said cell's proliferation in presence of the known melatonin-signaling pathway agonist. 
     
     
         21 . The method of  claim 12 , wherein said impairment is detected by a reduction of inhibition of osteoclasts resorption activity by the known melatonin-signaling pathway agonist, and wherein the candidate compound is selected if said reduction of inhibition of osteoclasts resorption activity is inhibited in the presence of the candidate compound as compared to that in the absence thereof. 
     
     
         22 . The method of  claim 12 , wherein said cells are selected from the group consisting of osteoblasts, osteoclasts, lymphocytes, monocytes and myoblasts. 
     
     
         23 . The method of  claim 12 , wherein said cells are blood cells. 
     
     
         24 . The method of  claim 12 , wherein said cells are lymphocytes.