Abstract
SCLEROSTIN (Sost) is expressed predominantly in osteocytes acting as a negative regulator of bone formation. In humans, mutations in the SOST gene lead to skeletal overgrowth and increased bone mineral density, suggesting that SCLEROSTIN is a key regulator of bone mass. The function of SCLEROSTIN as an inhibitor of bone formation is further supported by Sost knockout (KO) mice which display a high bone mass with elevated bone formation. Previous studies have indicated that Sost exerts its effect on bone formation through Wnt-mediated regulation of osteoblast differentiation, proliferation, and activity. Recent in vitro studies have also suggested that SCLEROSTIN regulates angiogenesis and osteoblast-to-osteocyte transition. Despite this wealth of knowledge of the mechanisms responsible for SCLEROSTIN action, no previous studies have examined whether SCLEROSTIN regulates osteocyte and vascular configuration in cortices of mouse tibia. Herein, we image tibiae from Sost KO mice and their wild-type (WT) counterparts with high-resolution CT to examine whether lack of SCLEROSTIN influences the morphometric properties of lacunae and vascular canal porosity relating to osteocytes and vessels within cortical bone. Male Sost KO and WT mice (n = 6/group) were sacrificed at 12 weeks of age. Fixed tibiae were analyzed using microCT to examine cortical bone mass and architecture. Then, samples were imaged by using benchtop and synchrotron nano-computed tomography at the tibiofibular junction. Our data, consistent with previous studies show that, Sost deficiency leads to significant enhancement of bone mass by cortical thickening and bigger cross-sectional area and we find that this occurs without modifications of tibial ellipticity, a measure of bone shape. In addition, our data show that there are no significant differences in any lacunar or vascular morphometric or geometric parameters between Sost KO mouse tibia and WT counterparts. We, therefore, conclude that the significant increases in bone mass induced by Sost deficiency are not accompanied by any significant modification in the density, organization, or shape of osteocyte lacunae or vascular content within the cortical bone. These data may imply that SCLEROSTIN does not modify the frequency of osteocytogenic recruitment of osteoblasts to initiate terminal osteocytic differentiation in mice.
Highlights
Bone is a metabolically active tissue constantly adapting its structure to external mechanical stimuli, leading to changes in mass (Raab et al, 1991; Bennell et al, 2002), shape (Rubin, 1984), strength (Järvinen et al, 2003; Leppänen et al, 2008), and length (Howell, 1917; Steinberg and Trueta, 1981)
We found that Sost deficiency did not alter tibial length (Table 1) but was a significant determinant of bone cross-sectional area (CSA) (Figure 1B), producing higher bone CSA in Sost KO compared with WT mice along the entire tibia length
We found that Sost deficiency contributed significantly to cortical thickness (Figures 1A,B), with Sost KO mice exhibiting higher thickness than WT mice
Summary
Bone is a metabolically active tissue constantly adapting its structure to external mechanical stimuli, leading to changes in mass (Raab et al, 1991; Bennell et al, 2002), shape (Rubin, 1984), strength (Järvinen et al, 2003; Leppänen et al, 2008), and length (Howell, 1917; Steinberg and Trueta, 1981). Osteocytes, the most abundant cells within skeleton, are derived by a process termed osteocytogenesis from bone-forming osteoblasts. They reside within irregularly shaped ellipsoidal lacunar spaces (FranzOdendaal et al, 2006) and are reported to act as strain sensors and transducers (Bonewald and Johnson, 2008; Javaheri et al, 2014). An alternative proposes that osteocytes are vital for efficient bone remodeling and repair of bone microdamage (Verborgt et al, 2000; Ma et al, 2008) Besides these roles, osteocytes are reported to regulate matrix mineral homeostasis (Qing and Bonewald, 2009) through osteocytic osteolysis (Bélanger, 1969; Kerschnitzki et al, 2013)
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