Bone loss and increased bone marrow adiposity in ovary-intact and ovariectomized rats with chronic obstructive pulmonary disease.

Abstract

Objective: Osteoporosis is a major clinically significant extrapulmonary comorbidity that can arise in individuals with chronic obstructive pulmonary disease (COPD). While there have been reports of a negative correlation between bone marrow adiposity and bone integrity, the role of such adiposity in COPD-induced bone loss is not well understood. This study was developed with the aim of clarifying how COPD affects bone and bone marrow fat in both ovary-intact and ovariectomized (OVX) rats.

Methods: This study utilized 32 five-month-old female Wistar rats that either underwent bilateral OVX or Sham surgical procedures. Beginning 7 days after surgery, these rats were regularly exposed to cigarette smoke (CS) or room air (RA) for 5 months. At baseline, 3 months, and 5 months, a series of parameters were analyzed including the bone marrow fat fraction (FF) and bone mineral density (BMD) for the left proximal femur and L4-L5 vertebrae, as measured through water/fat MRI and dual-energy X-ray absorptiometry. Moreover, pulmonary function, lung morphometry, marrow adipocyte characteristics detected via histopathology, trabecular bone microarchitectural features detected by micro-CT scanning, changes in adipogenic and osteogenic marker gene expression detected by qPCR, and serum levels of bone turnover biomarkers detected by ELISA were also analyzed.

Results: CS exposure for 5 months was associated with the significant exacerbation of fat expansion in the bone marrow together with overall bone deterioration in the ovary-intact and OVX rats. Relative to rats exposed to RA, those exposed to CS presented with: (1) Increased marrow FF, larger marrow adipocyte diameter, greater adipocyte density, and a higher adipocyte volume percentage; (2) an increase in the expression of adipogenic genes (PPARγ2, FABP4) in the bone marrow; (3) trabecular bone microstructural deterioration, reduced BMD, lower levels of osteogenic gene expression (Runx2), and changes in the levels of serum bone biomarkers including decreased bone formation marker levels together with increased levels of markers of bone resorption. The combination of chronic CS exposure and OVX was associated with even more pronounced fat expansion in the bone marrow and bone loss relative to CS exposure in isolation. Over time, CS exposure was associated with the progressive accumulation of fat in the bone marrow and the deterioration of bone tissue, with marrow FF differing significantly within 3 months of CS exposure, while BMD was significantly decreased by month 5 relative to RA-exposed control rats.

Conclusion: These results suggest that bone marrow adiposity is closely associated with the onset of osteoporosis among female rats in this model of COPD, with likely effects on the activity of both osteoblasts and osteoclasts. These results underscore the importance of targeting adipose cells in the bone marrow when seeking to more effectively manage osteoporosis among patients with COPD.