Thermoneutral housing attenuates premature cancellous bone loss in male C57BL/6J mice

Abstract

Mice are a commonly used model to investigate aging-related bone loss but, in contrast to humans, mice exhibit cancellous bone loss prior to skeletal maturity. The mechanisms mediating premature bone loss are not well established. However, our previous work in female mice suggests housing temperature is a critical factor. Premature cancellous bone loss was prevented in female C57BL/6J mice by housing the animals at thermoneutral temperature (where basal rate of energy production is at equilibrium with heat loss). In the present study, we determined if the protective effects of thermoneutral housing extend to males. Male C57BL/6J mice were housed at standard room temperature (22°C) or thermoneutral (32°C) conditions from 5 (rapidly growing) to 16 (slowly growing) weeks of age. Mice housed at room temperature exhibited reductions in cancellous bone volume fraction in distal femur metaphysis and fifth lumbar vertebra; these effects were abolished at thermoneutral conditions. Mice housed at thermoneutral temperature had higher levels of bone formation in distal femur (based on histomorphometry) and globally (serum osteocalcin), and lower global levels of bone resorption (serum C-terminal telopeptide of type I collagen) compared to mice housed at room temperature. Thermoneutral housing had no impact on bone marrow adiposity but resulted in higher abdominal white adipose tissue and serum leptin. The overall magnitude of room temperature housing-induced cancellous bone loss did not differ between male (current study) and female (published data) mice. These findings highlight housing temperature as a critical experimental variable in studies using mice of either sex to investigate aging-related changes in bone metabolism.

Effects of Propranolol on Bone, White Adipose Tissue, and Bone Marrow Adipose Tissue in Mice Housed at Room Temperature or Thermoneutral Temperature

“…The lower levels of bMAT and lower levels of cancellous bone observed in female mice housed at room temperature appear consistent with a shared mechanism. However, a different response occurred in male mice; whereas premature cancellous bone loss was evident in males housed at room temperature, differences in bMAT were not observed (6). The divergent response of bMAT to room temperatureinduced cold stress in female and male mice does not support a shared mechanism.…”

“…The bone loss is not uniform, with more loss occurring in long bones than in lumbar vertebrae (7,33) and in the distal femur, more loss occurring in metaphysis than in epiphysis (34). Importantly, housing mice at thermoneutrality prevents premature bone loss (6,7). In female mice, changes in bMAT levels in response to differences in housing temperature follow a similar pattern in that the bMAT levels are lower in distal femur metaphysis of mice housed at room temperature (7).…”

“…When housed at room temperature, C57BL/6 mice of both sexes exhibit rapid loss of cancellous bone prior to cessation of linear bone growth (5)(6)(7). Importantly, housing mice at thermoneutrality prevents the premature bone loss (6,7).…”

“…When housed at room temperature, C57BL/6 mice of both sexes exhibit rapid loss of cancellous bone prior to cessation of linear bone growth (5)(6)(7). Importantly, housing mice at thermoneutrality prevents the premature bone loss (6,7). The lower cancellous bone volume fraction in distal femur of mice housed at room temperature compared to mice housed at thermoneutrality is due, in part, to decreased bone formation; osteoblast-lined bone perimeter, bone formation rate measured using fluorochrome labels, mRNA levels for bone matrix proteins, and serum osteocalcin are lower in mice housed at room temperature.…”

“…Bone formation and cancellous bone volume fraction are often inversely associated with bone marrow adiposity (8)(9)(10)(11)(12)(13)(14)(15). However, an inverse relationship was not observed with housing temperature; female mice housed at room temperature had lower bone formation as well as lower bMAT compared to mice housed at thermoneutrality, whereas male mice had lower bone formation but did not exhibit differences in bMAT (6,7).…”