downstream of RANK during osteoclastogenesis

Shwachman-Diamond syndrome (SDS) re-sults from mutations in the SBDS gene, characterized by exocrine pancreatic in-sufficiency and hematologic and skeletal abnormalities. Neutropenia and neutro-phil dysfunction are hallmark features of SDS; however, causes for the bone de-fects are unknown. Dysfunction of bone-resorbing osteoclasts, formed by the fu-sion of monocytic progenitors derived from the same granulocytic precursors as neutrophils, could be responsible. We report that Sbds is required for in vitro and in vivo osteoclastogenesis (OCG). Sbds-null murine monocytes formed oste-oclasts of reduced number and size be-cause of impaired migration and fusion required for OCG. Phenotypically, Sbds-null mice exhibited low-turnover osteopo-rosis consistent with findings in SDS patients. Western blotting of Rho GT-Pases that control actin dynamics and migration showed a 5-fold decrease in Rac2, whereas Rac1, Cdc42, and RhoA were unchanged or only mildly reduced. Although migration was rescued on Rac2 supplementation, OCG was not. This was attributed to impaired signaling down-stream of receptor activator of nuclear factor-B (RANK) and reduced expres-sion of the RANK-ligand-dependent fu-sion receptor DC-STAMP. We conclude that Sbds is required for OCG by regulat-ing monocyte migration via Rac2 and osteoclast differentiation signaling down-stream of RANK. Impaired osteoclast for-mation could disrupt bone homeostasis, resulting in skeletal abnormalities seen in SDS patients. (Blood. 2011;117(6): 2044-2053