Compositions and methods for modulating bone mineral deposition
AssigneesThe Regents of the University of California, The Burnham Institute
InventorsJose Luis Millan, Robert Terkeltaub
Life of this patent
Estimating the term…
Abstract
The key function of TNAP in bone is degradation of PPi to remove this mineralization inhibitor and provide free phosphate for apatite deposition. PC-1 is a direct antagonist of TNAP function. ANK also antagonizes TNAP-dependent matrix calcification. Specifically, the activity of PC-1 inhibits initial MV apatite deposition, but ANK inhibits propagation of apatite outside the MVs. Furthermore, loss of function of the two distinct skeletal TNAP antagonists, PC-1 and ANK, ameliorates TNAP deficiency-associated osteomalacia in vivo. Conversely, the hyperossification associated with both PC-1 null mice and ANK-deficient (ank/ank) mice is ameliorated by deficiency of TNAP in vivo.
Claims66
A method for decreasing matrix mineralization in a tissue of a patient having insufficient or deficient ANK activity or expression, comprising administering an amount of a TNAP inhibtor to the tissue or patient effective to inhibit TNAP expression or activity.
A method for increasing matrix mineralization in a tissue of a patient having insufficient or deficient TNAP activity or expression, comprising administering an amount of an ANK inhibitor to the tissue or patient effective to inhibit ANK expression or activity.
A method of treating a patient having hypophosphatasia comprising administering a compound that reduces expression or an activity of ANK in a tissue of the patient affected by the hypophosphatasia.
A method of treating a patient having a disease selected from the group consisting of arterial calcification, ankylosing spondylitis, ossification of the posterior longitudinal ligament, myositis ossificans, diffuse idiopathic skeletal hyperostosis, calcific tendonitis, rotator cuff disease of the shoulders, osteomalacia, metabolic bone disease associated with renal failure, bone spurs, cartilage or ligament degeneration due to hydroxyapatite crystal deposition, chondrocalcinosis and osteoporosis, caused at least in part by deficient ANK activity of expression, comprising administering a compund that reduces expression or an activity of TNAP in a tissue of the patient affected by the disease.
A kit comprising an amount of a TNAP inhibitor effective to reduce matrix mineralization in a tissue of a patient having deficient ANK activity or expression, and instructions for administering said inhibitor to said patient on a label or packaging insert.
A kit comprising an amount of an ANK or OPN inhibitor effective to increase matrix mineralization in a tissue of a patient having deficient TNAP activity or expression, and instructions for administering said inhibitor to said patient on a label or packaging insert.
A method of identifying a compound useful in treating a disorder associated with insufficient or deficient ANK activity or expression comprising:
- a) providing an animal having deficient ANK activity or expression, wherein the animal has excessive mineralization in one or more tissues;
- b) administering a test compound that inhibits TNAP expression or an activity to the animal;
- c) determining if the animal exhibits an improvement in a tissue that has excessive mineralization,
- wherein an improvement in the tissue identifies the test compound as a compound useful in treating a disorder associated with insufficient or deficient ANK activity or expression.
A method of identifying a compound useful in treating a disorder associated with insufficient or deficient TNAP activity or expression comprising:
- a) providing an animal having deficient TNAP activity or expression, wherein the animal has deficient mineralization in one or more tissues;
- b) administering a test compound that inhibits ANK or OPN expression or an activity to the animal;
- c) determining if the animal exhibits an improvement in a tissue that has deficient mineralization,
- wherein an improvement in the tissue identifies the test compound as a compound useful in treating a disorder associated with insufficient or deficient TNAP activity or expression.
A method for treating a disorder or disease associated with insufficient or deficient ANK or PC-1 activity or expression, comprising administering an amount of OPN to the tissue or patient effective to inhibit matrix mineralization of the tissue.
A method for decreasing matrix mineralization in a tissue of a patient having insufficient or deficient ANK or PC-1 activity or expression, comprising administering an amount of OPN to the tissue or patient effective to inhibit matrix mineralization of the tissue.
A method of treating a patient having hypophosphatasia comprising administering a compound that reduces expression or an activity of OPN in a tissue of the patient affected by the hypophosphatasia.
A method of treating a patient having hyperphosphatasia comprising administering a compound that increases expression or an activity of OPN in a tissue of the patient affected by the hyperphosphatasia.
A method of identifying a patient having or at risk of having hypophosphatasia or a disorder associated with hypophosphatasia comprising:
- a) providing a patient or a sample from a patient;
- and
- b) assaying the patient or sample from the patient or the sample for the amount of OPN,
- wherein an amount of OPN greater than normal indicates the presence of hypophosphatasia or an increased risk of hypophosphatasia.
A method of identifying a patient in need of treatment for hypophosphatasia or a disorder associated with hypophosphatasia comprising:
- a) providing a patient or a sample from a patient;
- and
- b) assaying the patient or sample from the patient or the sample for the amount of OPN,
- wherein an amount of OPN greater than normal indicates the presence of hypophosphatasia or an increased risk of hypophosphatasia.
A method of identifying a patient having or at risk of having hyperphosphatasia or a disorder associated with hyperphosphatasia comprising:
- a) providing a patient or a sample from a patient;
- and
- b) assaying the patient or sample from the patient or the sample for the amount of OPN,
- wherein an amount of OPN less than normal indicates the presence of hyperphosphatasia or an increased risk of hyperphosphatasia.
A method of identifying a patient in need of treatment for hyperphosphatasia or a disorder associated with hyperphosphatasia comprising:
- a) providing a patient or a sample from a patient;
- and
- b) assaying the patient or sample from the patient or the sample for the amount of OPN,
- wherein an amount of OPN less than normal indicates the presence of hyperphosphatasia or an increased risk of hyperphosphatasia.
A method of monitoring a patient receiving a treatment that inhibits PC- I or ANK expression or activity comprising:
- a) providing a patient or a sample from a patient;
- and
- b) assaying the patient or sample from the patient or the sample for the amount of OPN,
- wherein a decreased amount of OPN after treatment indicates that the treatment has inhibited PC-1 or ANK.
A method of monitoring a patient receiving a treatment that increases PC-1 or ANK expression or activity comprising:
- a) providing a patient or a sample from a patient;
- and
- b) assaying the patient or sample from the patient or the sample for the amount of OPN,
- wherein an increased amount of OPN after treatment indicates that the treatment increases PC-1 or ANK.
A method of identifying a compound that modulates PC-1, ANK or TNAP expression or activity comprising:
- a) administering a test compound to a cell or animal;
- and
- b) determining if the cell or animal exhibits an increase or a decrease in OPN expression or activity,
- wherein an increase or decrease in OPN expression or activity identifies the test compound as a compound that modulates PC-1, ANK or TNAP expression or activity.
A method of identifying candidate compounds for treating hypermineralization or hypomineralization comprising:
- a) administering a test compound to a cell or animal;
- and
- b) determining if the cell or animal exhibits an increase or a decrease in OPN expression or activity,
- wherein an increase or decrease in OPN expression or activity identifies the test compound as a candidate compound for treating hypermineralization or hypomineralization.
A method of monitoring a patient receiving a treatment that modulates TNAP expression or activity comprising:
- a) providing a patient or a sample from a patient;
- and
- b) assaying the patient or sample from the patient or the sample for the amount of OPN,
- wherein an increased or decreased amount of OPN after treatment indicates that the treatment modulates TNAP expression or activity.
Dependencies are inferred from the claim text.