Chagin AS, Chrysis D, Takigawa M, Ritzen EM, Sävendahl L.

Source

Pediatric Endocrinology Unit, Department of Woman and Child Health, Karolinska Institute, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. andrei.chagin@ki.se

Abstract

The importance of estrogens for the regulation of longitudinal bone growth is unequivocal. However, any local effect of estrogens in growth plate cartilage has been debated. Recently, several enzymes essential for estrogen synthesis were shown to be expressed in rat growth plate chondrocytes. Local production of 17beta-estradiol (E2) has also been demonstrated in rat costal chondrocytes. We aimed to determine the functional role of locally produced estrogen in growth plate cartilage. The human chondrocyte-like cell line HCS-2/8 was used to study estrogen effects on cell proliferation (3H-labeled thymidine uptake) and apoptosis (cell death detection ELISA kit). Chondrocyte production of E2 was measured by RIA and organ cultures of fetal rat metatarsal bones were used to study the effects of estrogen on longitudinal growth rate. We found that significant amounts of E2 were produced by HCS-2/8 chondrocytes (64.1 +/- 5.3 fmol/3 days/10(6) cells). The aromatase inhibitor letrozole (1 microM) and the pure estrogen receptor antagonist ICI 182,780 (10 microM) inhibited proliferation of HCS-2/8 chondrocytes by 20% (P < 0.01) and almost 50% (P < 0.001), respectively. Treatment with ICI 182,780 (10 microM) increased apoptosis by 228% (P < 0.05). Co-treatment with either caspase-3 or pan-caspase inhibitors completely blocked ICI 182,780-induced apoptosis (P < 0.001 vs ICI 182,780 only). Moreover, both ICI 182,780 (10 microM) and letrozole (1 microM) decreased longitudinal growth of fetal rat metatarsal bones after 7 days of culture (P < 0.01). In conclusion, our data clearly show that chondrocytes endogenously produce E2 and that locally produced estrogen stimulates chondrocyte proliferation and protects from spontaneous apoptosis. In addition, longitudinal growth is promoted by estrogens locally produced within the epiphyseal growth plate.

Analysis: What we have been learning about and sort of concluded from the months of research was that overall, estrogen was a bad thing and that to delay the final growth plate closure we have to take aromatase inhibitors to prevent estrogen from completely using up the last bit of chondrocytes left. This study actually seems to have the reverse conclusion, which is that estrogen is good for chondrocyte proliferation and thus longitudinal growth and that Letrozole and other estrogen receptor antagonists like ICI were not a good thing since they lead to more spontaneous chondrocyte apoptosis in the growth plate of young lab rats. However we are not talking about femurs and tibias, but digits, feet metatarsals. The growth plates themselves seem to create estrogen, specifically beta-estradiol (E2). The researchers conclude with “In conclusion, our data clearly show that chondrocytes endogenously produce E2 and that locally produced estrogen stimulates chondrocyte proliferation and protects from spontaneous apoptosis. In addition, longitudinal growth is promoted by estrogens locally produced within the epiphyseal growth plate.” If I was to try to guess at why this study has results that go directly in conflict with our main axiom on how growth works, I’d say this phenomena is similar to what you see when the onset of puberty starts. The increase in estrogen release rate happens in two stages in bone development, when the puberty stage first get started, and when the puberty is about to end. Since we are talking about rats that are very young still with functional growth plates, we could say that the experiment is similar to when they are going through the initial puberty stage. Remember that girls go through puberty earlier than boys so during the 4-6 grade years range, some girls actually become taller than boys. This is from the excess estrogen they got in the earlier years compared to boys  so they start puberty earlier. However we know from other studies that it seems that first (and 2nd) estrogen increased rate of release actually is what depletes the number of available chondrocytes in the resting zone that is ultimately able to proliferate and hypertrophy. This means that the height increase you get in the that stage is what will hurt you down the line when your resting zone runs out of proliferating material and ultimately will close faster. So, sometimes estrogen is a good thing and aromatase inhibitors are a bad thing in leading to longitudinal growth. However I caution that the initial good results you see could be the cause for bad results later on. I think this study never took the studies further to see if the experimental to the control groups still had the same ultimate metatarsal lengthening ratio or did the metatarsal length ratios of control to experimental reverse due to the excess estrogen in the beginning.