Genetic studies of bone diseases: evidence for involvement of DNA damage response proteins in bone remodeling.

Bone remodeling is carried out by bone marrow mesenchymal stem cell derived osteoblasts, which form the bones, and hematopoeitic stem cell derived osteoclasts, which absorb the bones. Their actions are coordinated in two ways: osteoblasts and their precursors synthesize and secrete cytokines such as RANKL and M-CSF to regulate osteoclastogenesis; bone resorption releases matrix associated TGF-β and BMPs to stimulate bone formation at the same sites. Recent studies on transgenic mouse models revealed that several proteins involved in the DNA damage response play important roles in bone remodeling. DNA damage response is triggered by double stranded DNA breaks, single stranded DNA breaks as well as other types of lesions, which recruit and activate Ser/Thr kinases such as Atm to the damaged sites, where Atm activates p53 to promote apoptosis, cell cycle arrest, and DNA repair. Atm also activates c-Abl, a non-receptor tyrosine kinase, to promote apoptosis. Studies from our and other laboratories have shown that c-Abl and Atm positively regulate osteoblast differentiation and bone formation and mice deficient for either of them show osteoporosis, whereas p53 negatively regulates osteoblast proliferation/differentiation and bone formation and the knockout mouse shows osteosclerosis. These three proteins have osteoblast autonomous effect without directly affecting osteoclast differentiation or resorption activity. Furthermore, they appear to regulate osteoblast differentiation through controlling the expression of osterix, an osteoblast specific transcription factor essential for osteoblast differentiation. These results establish a functional link between osteoblast differentiation and DNA damage response.