Development of tendon structure and function: regulation of collagen fibrillogenesis.

In the tendon, the development of mature mechanical properties is dependent on the assembly of a tendon-specific extracellular matrix. This matrix is synthesized by the tendon fibroblasts and composed of collagen fibrils organized as fibers, as well as fibril-associated collagenous and non-collagenous proteins. All of these components are integrated, during development and growth, to form a functional tissue. During tendon development, collagen fibrillogenesis and matrix assembly progress through multiple steps where each step is regulated independently, culminating in a structurally and functionally mature tissue. Collagen fibrillogenesis occurs in a series of extracellular compartments where fibril intermediates are assembled and mature fibrils grow through a process of post-depositional fusion of the intermediates. Linear and lateral fibril growth occurs after the immature fibril intermediates are incorporated into fibers. The processes are regulated by interactions of extracellular macromolecules with the fibrils. Interactions with quantitatively minor fibrillar collagens, fibril-associated collagens and proteoglycans influence different steps in fibrillogenesis and the extracellular microdomains provide a mechanism for the tendon fibroblasts to regulate these extracellular interactions.

Expression of type XIV collagen in developing chicken tendons: association with assembly and growth of collagen fibrils.

Collagen fibril assembly is a multistep process involving multiple macromolecular interactions. Type XIV collagen contains multiple domains and is capable of interacting with collagen fibrils and other extracellular matrix components. During tendon development, naturally changing expression of type XIV collagen and its variants may modulate such interactions. Type XIV collagen was studied using immunochemical and molecular approaches. Western analysis demonstrated that type XIV collagen content was high between days 14 and 19, decreasing sharply at hatching. Immunoelectron microscopy demonstrated that type XIV collagen was fibril-associated, with a periodicity of 67 nm, indicating specific interactions. Decreased fibril-associated reactivity for type XIV collagen was seen at hatching, indicating a removal of collagen XIV from the fibril surface. The expression of two NC1 splice variants was analyzed. Overall, type XIV collagen mRNA decreased significantly from day 14 to hatching. The long NC1 splice variant was the predominant species at 14 days; at 19 days the two variants were expressed in lower amounts at nearly a 1:1 ratio; at hatching, both variants were expressed minimally. Changes in splice variant expression, suggest that different functional forms of type XIV collagen are present, allowing modified interactions with fibrils during development. In conclusion, type XIV collagen is fibril-associated and developmentally regulated. Modulation of expression of the NC1 splice variants may mediate the fibril interactions that allow the transition from growing fibril intermediates to mature fibrils.

Effects of exposure to external ionizing radiation on cancer mortality in nuclear workers monitored for radiation at Rocketdyne/Atomics International.

BACKGROUND AND METHODS: A retrospective cohort study was conducted to estimate the effects of low-level exposure to external (penetrating) radiation on cancer mortality among 4,563 workers monitored for external radiation between 1950 and 1993 at a nuclear research and production facility in Southern California. RESULTS: Of the 875 deaths that occurred before 1995, 258 were due to cancer as the underlying cause. External comparisons of male subjects with the U.S. white male population indicated that the workers had lower rates of dying from all causes and all cancers, but a higher rate of dying from leukemia. Internal comparisons of workers exposed at different dose levels, using risk-set analyses with adjustment for confounders, demonstrated an increased mortality rate in workers exposed to 200 mSv for hemato- and lymphopoietic cancers and for lung cancer. Mortality rates for total cancers and "radiosensitive" solid cancers increased monotonically with cumulative radiation dose, but no trends were observed for "nonradiosensitive" cancers. CONCLUSIONS: Despite possible residual confounding and low precision for estimating effects on specific cancers, these findings indicate that chronic, low-level radiation exposure may have more generalized carcinogenic effects than have been observed in most previous investigations. Such effects may have become evident as a result of the relatively long follow-up period in the present study.