Abstract
Osteocytes play a central role in the regulation of bone remodeling. The aim of this study was to explore osteocyte function, and particularly the expression of SOST, a Wnt inhibitor, in patients with hip fractures. Serum sclerostin levels were measured by ELISA. The expression of several osteocytic genes was studied by quantitative PCR in trabecular samples of the femoral head of patients with hip fractures, hip osteoarthritis and control subjects. The presence of sclerostin protein and activated caspase 3 was revealed by immunostaining. There were no significant differences in serum sclerostin between the three groups. Patients with fractures have fewer lacunae occupied by osteocytes (60 ± 5% vs. 64 ± 6% in control subjects, P = 0.014) and higher numbers of osteocytes expressing activated caspase 3, a marker of apoptosis. The proportion of sclerostin-positive lacunae was lower in patients with fractures than in control subjects (34 ± 11% vs. 69 ± 10%, P = 2 × 10(-8)). The proportion of sclerostin-positive osteocytes was also lower in patients. RNA transcripts of SOST, FGF23 and PHEX were also less abundant in fractures than in control bones (P = 0.002, 5 × 10(-6), and 0.04, respectively). On the contrary, in patients with osteoarthritis, there was a decreased expression of SOST and FGF23, without differences in PHEX transcripts or osteocyte numbers. Osteocyte activity is altered in patients with hip fractures, with increased osteocyte apoptosis and reduced osteocyte numbers, as well as decreased transcription of osteocytic genes. Therefore, these results suggest that an osteocyte deficiency may play a role in the propensity to hip fractures.
Highlights
After the seminal studies showing that gain-of-function and loss-of-function mutations of the Wnt co-receptor lipoprotein related peptide 5 (LRP5) are associated with marked changes of opposite direction in bone mass, the Wnt pathway has been recognized as an important bone anabolic stimulus, influencing bone remodelling and fracture repair [1;2]
In this study we confirmed that sclerostin is abundantly expressed in human bone, where it was detected in osteocytes and osteocytic lacunae, but not in osteoblasts or other cells
Osteocytes derive from osteoblasts, which become embedded into bone matrix when new bone is laid down and stay there inside the osteocytic lacunae
Summary
After the seminal studies showing that gain-of-function and loss-of-function mutations of the Wnt co-receptor lipoprotein related peptide 5 (LRP5) are associated with marked changes of opposite direction in bone mass, the Wnt pathway has been recognized as an important bone anabolic stimulus, influencing bone remodelling and fracture repair [1;2]. Osteocytes are nowadays recognized as major players in the regulation of bone remodelling They are considered as the cells transducing the effects of mechanical forces acting on bone, able to mark the skeletal areas where a new remodelling cycle is to be initiated, and with strong influence on bone formation [5,6,7]. We have previously reported that, in comparison with patients with osteoarthritis (OA), the expression of a number of genes in the Wnt pathway is reduced in bone samples from patients with osteoporotic hip fractures, suggesting that differences in Wnt activity may be involved in the opposite changes in bone mass typical of these disorders. On the basis of those data, we hypothesized that an osteocyte dysfunction with increased expression of sclerostin could be involved in the reduced Wnt activity found in hip fractures
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