Control of postnatal bone mass by the zinc finger adapter protein Schnurri-3.
The completed skeleton undergoes continuous remodeling for the duration of adult life. Rates of bone formation by osteoblasts and bone resorption by osteoclasts determine adult bone mass. Abnormalities in either the osteoblast or osteoclast compartment affect bone mass and result in skeletal disorders, the most common of which is osteoporosis, a state of low bone mass. Much is known about the molecular control of bone formation and resorption from rare single gene disorders resulting in elevated or reduced bone mass. Such genetic disorders can be attributed either to osteoclast deficiencies, collectively termed "osteopetrosis," or to intrinsically elevated osteoblast activity, termed "osteosclerosis." However, an increasing need for anabolic therapies to prevent age-induced bone loss has stimulated a search for additional genes that act at the level of the osteoblast to regulate matrix synthesis. Recently, we have discovered a zinc finger adaptor protein called Schnurri-3 (Shn3) that potently regulates adult bone mass. Mice that lack Shn3 have normal skeletal morphogenesis but display profoundly elevated bone mass that increases with age. The molecular mechanism was revealed to be the recruitment of WWP1, a Nedd4 family E3 ubiquitin ligase, by Shn3 to the major transcriptional regulator of the osteoblast, Runx2. In the absence of Shn3, Runx2 degradation by WWP1 is inhibited resulting in increased levels of Runx2 protein and enhanced expression of Runx2 target genes leading to increased osteoblast synthetic activity. Small molecules that inhibit Shn3 or WWP1 may be attractive candidates for the treatment of diseases of low bone mass.
Glimcher
Laurie H
LH
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA. lglimche@hsph.harvard.edu
Jones
Dallas C
DC
Wein
Marc N
MN
D000818:Animals; D050659:Core Binding Factor Alpha 1 Subunit / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology*; D051379:Mice; D009929:Organ Size / Q000502:physiology*; D010012:Osteogenesis / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology
D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins; C493716:Runx2 protein, mouse; C510834:Schnurri-3 protein, mouse; C510836:WWP1 protein, mouse; D044767:Ubiquitin-Protein Ligases