f Endochondral ossification is a highly regulated process that relies on properly orchestrated cell-cell interactions in the developing growth plate. This study is focused on understanding the role of a crucial regulator of cell-cell interactions, the membrane-anchored metalloproteinase ADAM17, in endochondral ossification. ADAM17 releases growth factors, cytokines, and other membrane proteins from cells and is essential for epidermal growth factor receptor (EGFR) signaling and for processing tumor necrosis factor alpha. Here, we report that mice lacking ADAM17 in chondrocytes (A17⌬Ch) have a significantly expanded zone of hypertrophic chondrocytes in the growth plate and retarded growth of long bones. This abnormality is caused by an accumulation of the most terminally differentiated type of chondrocytes that produces a calcified matrix. Inactivation of ADAM17 in osteoclasts or endothelial cells does not affect the zone of hypertrophic chondrocytes, suggesting that the main role of ADAM17 in the growth plate is in chondrocytes. This notion is further supported by in vitro experiments showing enhanced hypertrophic differentiation of primary chondrocytes lacking Adam17. The enlarged zone of hypertrophic chondrocytes in A17⌬Ch mice resembles that described in mice with mutant EGFR signaling or lack of its ligand transforming growth factor ␣ (TGF␣), suggesting that ADAM17 regulates terminal differentiation of chondrocytes during endochondral ossification by activating the TGF␣/EGFR signaling axis. Skeletal development is crucial to ensure optimal mobility and breathing, as well as protection of vital organs, such as the brain, spinal cord, lung, and heart. The axial and appendicular skeletons are formed through the generation of a cartilage intermediate, a process known as endochondral ossification, whereas the skull and clavicles are formed through intramembranous ossification (1-3). In the limb bud, which can be used as a model, endochondral ossification is initiated when mesenchymal precursor cells condense and the most central chondrocytes begin to differentiate. Eventually, this gives rise to different zones of chondrocytes in the growth plate, beginning with the resting zone, followed by the proliferating zone and the hypertrophic zone, in which chondrocytes secrete a type X collagen-rich matrix (1, 2). Once the hypertrophic chondrocytes mature into a terminally differentiated state and the lowermost cell layer becomes surrounded by mineral, the hypertrophic chondrocytes undergo apoptosis. This area in the developing long bone is directly adjacent to the primary center of ossification and is remodeled into trabecular bone as the invading vasculature supports the influx of osteoblasts and osteoclasts. In this process, the calcified matrix laid down by the hypertrophic chondrocytes is thought to be degraded through proteolytic activities, including MMP13 and MMP9 (4), while the remaining matrix provides a scaffold for the formation of trabecular bone. A secondary center of ossification develops after birth in m...

A B S T R A C T PurposeChildren with acute lymphoblastic leukemia (ALL) are often cured, but the therapies they receive may be neurotoxic. Little is known about the incidence and severity of late-occurring neurologic sequelae in ALL survivors. Data were analyzed to determine the incidence of adverse long-term neurologic outcomes and treatment-related risk factors. Patients and MethodsWe analyzed adverse neurologic outcomes that occurred after diagnosis in 4,151 adult survivors of childhood ALL who participated in the Childhood Cancer Survivor Study (CCSS), a retrospective cohort of 5-year survivors of childhood cancer diagnosed between 1970 and 1986. A randomly selected cohort of the survivors' siblings served as a comparison group. Self-reported auditoryvestibular-visual sensory deficits, focal neurologic dysfunction, seizures, and serious headaches were assessed. ResultsThe median age at outcome assessment was 20.2 years for survivors. The median follow-up time to death or last survey since ALL diagnosis was 14.1 years. Of the survivors, 64.5% received cranial radiation and 94% received intrathecal chemotherapy. Compared with the sibling cohort, survivors were at elevated risk for late-onset auditory-vestibular-visual sensory deficits (rate ratio [RR], 1.8; 95% CI, 1.5 to 2.2), coordination problems (RR, 4.1; 95% CI, 3.1 to 5.3), motor problems (RR, 5.0; 95% CI, 3.8 to 6.7), seizures (RR, 4.6; 95% CI, 3.4 to 6.2), and headaches (RR, 1.6; 95% CI, 1.4 to 1.7). In multivariable analysis, relapse was the most influential factor that increased risk of late neurologic complications. ConclusionChildren treated with regimens that include cranial radiation for ALL and those who suffer a relapse are at increased risk for late-onset neurologic sequelae.

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Purpose Mice lacking ADAM10 in endothelial cells (Adam10ΔEC mice) have shorter femurs, tibiae and humeri than controls, raising questions about how endothelial cells could control long bone growth. Methods We performed a histopathological evaluation of the femur and tibia growth plates at different postnatal stages, and assessed the distribution of TRAP-positive osteoclasts and endothelial cells at the growth plate. Results The growth plates in Adam10ΔEC mice appeared normal at P7 and P14, but a thickened zone of hypertrophic chondrocytes and increased trabecular bone density were apparent by P21 and later. The number of TRAP+ cells at the COJ was normal at P7 and P14, but was strongly reduced at P21 and later. Moreover, the density of endomucin-stained endothelial cells at the COJ was increased starting at P7. Conclusion The defects in long bone growth in Adam10ΔEC mice could be caused by a lack of osteoclastogenesis at the COJ. Moreover, ADAM10 appears to regulate endothelial cell organization in the developing bone vasculature, perhaps in a similar manner as in the developing retinal vascular tree, where ADAM10 is thought to control Notch-dependent endothelial cell fate decisions. This study provides evidence for the regulation of osteoclast function by endothelial cells in vivo.