McKay Orthopaedic Research Laboratory > Liu Lab > Ongoing Research

Skeletal Changes during Lactation and After Weaning (Collaborative Project with Dr. Wysolmerski group, Yale University School of Medicine)       Lactation induces substantial changes in maternal calcium and bone metabolism, as the mother's skeleton serves as a major source of calcium in milk production. During lactation, there is a dramatic increase in the rate of maternal bone resorption and in maternal skeletal calcium loss. Although the rate of bone formation is increased during this time, it is outpaced by the rate of bone resorption, resulting in a rapid net decline in bone mass. Despite the dramatic bone loss that occurs during lactation, bone mineral density is rapidly restored after weaning. Studies on rats have shown partial or full recovery of bone mass and mechanical properties after weaning. Using micro-computed tomography (µCT) and finite element (FE) modeling techniques, we observed a full recovery of trabecular bone volume fraction (BV/TV), 3D microarchitecture, and stiffness at lumbar vertebrae in mice after weaning.      We are interested in the cellular mechanisms behind the rapid but reversible bone loss that occurs during lactation. This may lead to findings of a new bone loss mechanism, which, in contrast to the well studied osteoclast resorption mechanism, could regulate calcium homeostasis in a more efficient way by not breaking down the organic bone matrix component. The most remarkable hormonal changes that occur during lactation are estrogen deficiency and circulation of PTH-related protein (PTHrP). Understanding their functions of regulating calcium homeostasis during lactation and weaning may lead to new insight into therapeutic strategies for estrogen-deficient human skeletons and cancer-related bone lesions.
	3D Dynamic Simulation of Bone Remodeling       The human skeleton is renewed continuously throughout one's entire life via the bone remodeling process. This process consists of a coupling of bone resorption by osteoclasts and bone formation by osteoblasts through basic multicellular units. Through this process, cracks and damaged tissue are removed and regenerated. Conversely, excessive remodeling is associated with bone structure deterioration and leads to fragility fractures.      We are interested in developing a three-dimensional (3D) bone remodeling simulation to model the dynamic osteoclast resorption and coupled osteoblast formation process on µCT images of trabecular bone. Our work has shown that with all the physiological parameters such as activation frequency and 3D morphology of resorption cavities strictly based on bone biopsy measurements, this simulation can predict the menopausal bone loss pattern in human spine and femoral neck. The combination of advanced in vivo imaging technologies and a novel bone remodeling simulation technique will be an excellent tool for studying bone remodeling and adaptation mechanisms under different pathological or treatment conditions. After this pre-clinical system is validated using a rodent model, it can also be extended to a clinical setting to improve the diagnosis strategies for osteoporosis and fracture prediction. Furthermore, the system can be used to study mechanisms of new therapies and evaluate treatment efficiency.
Temporal and Spatial Changes in Bone Tissue Mineral Density Distribution in Chronic Kidney Disease (Collaborative Project with Dr. Thomas Nickolas, Columbia University Medical Center)       Fractures are extraordinarily common across the spectrum of chronic kidney disease (CKD). By transiliac crest bone biopsy, biochemical, and high resolution peripheral QCT (HR-pQCT) studies, several distinctive abnormalities of bone quality in CKD, including both abnormally elevated and depressed bone turnover, cortical thinning and porosity, trabecular microarchitectural deterioration, and lower bone stiffness have been identified. However, the decrease in bone strength caused by loss of bone mass and deterioration of bone microarchitecture cannot fully account for the increased risk of fractures in CKD. Other aspects of bone quality, such as bone tissue mineral density (TMD), may also be significantly altered in CKD, leading to bone fragility.      Recently we have developed an image analysis technique that utilizes HR-pQCT and a calibration phantom to obtain data on bone tissue mineralization noninvasively. This method quantifies both the level of bone tissue mineralization and its 3D distribution in the cortical and trabecular compartments. Our preliminary studies demonstrated that trabecular bone TMD was lower in CKD patients than in controls and was inversely associated with serum calciotropic hormones and bone turnover markers. Now, the availability of longitudinal HR-pQCT scans and the application of advanced image registration techniques enable us to monitor noninvasively the temporal and spatial changes in bone TMD associated with CKD and its progression. This technology has tremendous potential to provide insight into both the pathogenesis of bone fragility and to inform the development of pharmaceutical agents that prevent fracture in the population of patients with CKD.	(Top) Clinical HR-pQCT scans of highly resolved microstructural images of distal radial bone; (Bottom) Changes in tissue mineralization of registered baseline and 2-year followup scans of a stage 4 CKD patient. Red represents decreases in bone mineral density and the green represents increases.
Imaging the effect of parathyroid hormone on basic multicellular unit of bone remodeling using registered micro computed tomography and histology (Collaborative Project with Dr. Ling Qin in McKay ORL)      Human skeleton constantly undergoes remodeling for maintaining skeletal integrity through basic multicellular unit (BMU). BMU consists of bone-resorbing osteoclasts excavating cavities on bone surface to remove aged or damaged bone tissue, and bone-forming osteoblasts laying down new bone matrix to refill the cavities. Daily parathyroid hormone (PTH) injection is the only FDA-approved anabolic treatment for osteoporosis that stimulates both bone formation and resorption with greater impact on formation. The 2D histology section is currently the only means to image the BMU activity; however, it cannot be used to monitor 3D temporal changes in BMU. How PTH regulates bone remodeling and BMU structure is not fully understood. Our lab is interested to employ new imaging approaches, such as in vivo µCT, histology, and image registration to examine the effect of PTH on bone remodeling and BMU structure in ovariectomized (OVX) rat model, the only FDA-approved rodent model mimicking human postmenopausal osteoporosis. The mechanistic insight developed from this animal-based study may be translated to clinical investigations of PTH in treating various metabolic bone diseases.