Methods for modulating skeletal remodeling and patterning by modulating SHN2 activity, SHN3 activity, or SHN2 and SHN3 activity in combination

Patent metadata

Field	Value
Publication number	US-9745589-B2
Application number	US-201113521709-A
Country	US
Kind code	B2
Filing date	Jan 13, 2011
Priority date	Jan 14, 2010
Publication date	Aug 29, 2017
Grant date	Aug 29, 2017

Abstract

This invention is based, at least in part, on the discovery that Shn2 and Shn3 play an important role in skeletal remodeling and skeletal patterning. Accordingly, the present invention provides methods for identifying medulators of Shn2 activity and methods for modulating bone formation and mineralization and Shn2-associated disorders using agents that modulate Shn2 expression and/or activity, in addition to methods for modulating Shn2 and Shn3.

First claim

What is claimed is:

1. A method for increasing trabecular bone formation and mineralization in the diaphysis of a bone, comprising
contacting an osteoblast with a first agent that decreases expression of Schnurri-2 (Shn2) in the osteoblast wherein the first agent is selected from the group consisting of: a nucleic acid molecule that is antisense to a Shn2 molecule, a Shn2 small interfering RNA (siRNA) molecule, a dominant negative Shn2 molecule, or combinations thereof, and
contacting the osteoblast with a second agent that decreases expression of Schnurri-3 (Shn3) in the osteoblast, wherein the second agent is selected from the group consisting of: a nucleic acid molecule that is antisense to a Shn3 molecule, a Shn3 siRNA molecule, a dominant negative Shn3 molecule, or combinations thereof,
wherein decreased expression of both Shn2 and Shn3 increases trabecular bone formation and mineralization in the diaphysis of the bone relative to decreased expression of Shn3 alone.

2. A method for treating a disease, disorder, condition, or injury that would benefit from increased trabecular bone formation and mineralization in the diaphysis of a bone in a subject in need thereof, comprising
contacting an osteoblast from the subject with a first agent that decreases the expression of Schnurri-2 (Shn2) in the osteoblast wherein the first agent is selected from the group consisting of: a nucleic acid molecule that is antisense to a Shn2 molecule, a Shn2 small interfering RNA (siRNA) molecule, a dominant negative Shn2 molecule, or combinations thereof, and
contacting the osteoblast with a second agent that decreases expression of Schnurri-3 (Shn3) in the osteoblast, wherein the second agent is selected from the group consisting of: a nucleic acid molecule that is antisense to a Shn3 molecule, a Shn3 siRNA molecule, a dominant negative Shn3 molecule, or combinations thereof,
wherein decreased expression of both Shn2 and Shn3 increases trabecular bone formation and mineralization in the diaphysis of the bone in the subject relative to decreased expression of Shn3 alone.

3. The method of claim 2 , wherein the step of contacting the osteoblast with an agent that decreases the expression of Shn3 in the osteoblast occurs in vitro.

4. The method of claim 2 , wherein the step of contacting the osteoblast with an agent that decreases the expression of Shn3 in the osteoblast occurs in vivo.

5. The method of claim 3 or 4 , wherein the agent is present on a surface.

6. The method of claim 2 , wherein the disease, disorder, condition, or injury is selected from the group consisting of: osteoporosis, osteopenia, osteomalacia, and osteitis deformans (Paget's disease of bone), osteoarthritis and inflammatory arthritides characterized by bone loss or excess bone formation including for example rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis.

7. The method of claim 2 , wherein the step of contacting the osteoblast with an agent that decreases the expression of Shn2 in the osteoblast occurs in vitro.

8. The method of claim 2 , wherein the step of contacting the osteoblast with an agent that decreases the expression of Shn2 in the osteoblast occurs in vivo.

Assignees

• Glimcher Laurie H
• Jones Dallas C
• Wein Marc
• Univ Cornell

Inventors

• Glimcher Laurie H
• Jones Dallas C
• Wein Marc

Classifications

• A61K38/1709

  from mammals · CPC title

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title

• A61K31/7088

  Compounds having three or more nucleosides or nucleotides · CPC title

• G01N2800/105

  Osteoarthritis, e.g. cartilage alteration, hypertrophy of bone · CPC title

• G01N2500/00

  Screening for compounds of potential therapeutic value · CPC title