Proteoglycans and age-related deterioration of bone toughness

Bone fragility fractures are a major concern of health care of rapidly aging populations due to the high



risk of long-term disability and even mortality. Such fractures are not only due to loss of bone mineral density



(BMD), but also due to adverse changes at different structural hierarchies of bone, including ultrastructural



changes observed in bone disorders (e.g. osteogenesis imperfecta, mucopolysaccharidosis, and age-related



osteopenia/ osteoporosis). However, the underlying mechanisms are still poorly understood. At the ultrastructural



level, bone is comprised of mineral, collagen, water, non-collagenous proteins (NCPs). Among the NCPs,



proteoglycans (PGs) containing glycosaminoglycans (GAGs) have a great potential in attracting and retaining



water in bone matrix. This is important because water plays a crucial role in plasticizing and toughening the



tissue. To this end, this study is performed to test the hypotheses that: (1) GAGs/PGs play a pivotal role in



toughening bone tissues via retaining bound water in bone matrix; and (2) the amount and/or type(s) of PGs



change with increasing age and such changes (e.g. decreased amount of GAGs) are a key factor that leads to the



age-related deterioration of bone quality. To test the hypotheses, two specific aims are proposed: Aim 1:



Determine whether proteoglycans (PGs) play a key role in imparting the toughness to bone. Here, biochemical



assays, mass spectrometry, low-field NMR, and nanoscratch and other mechanical test techniques will be sued to



determine (1) the role of PGs in attracting/retaining water (i.e. bound water) in bone matrix; (2) its contribution to



the in situ and bulk toughness of bone using an ex vivo (human cadaver bone) model and in vivo mouse models



(biglycan, decorin, and biglycan/decorin single and double knockout). Aim 2: Determine the role of PGs in the



age related reduction of cortical and trabecular bone quality in both genders. In Aim 2, an ex vivo model (i.e.



human cadaver bone from young, mid-aged, and elderly groups) will be used to determine the age-related changes



in the amount and structure of GAGs and PGs in bone matrix and the contribution of such changes to the



age-related deterioration in bone quality of both cortical and trabecular bone tissues at both ultrastructural and



bulk levels. In addition, sex-dependent differences in the age-related changes in matrix PGs and its contribution to



the associated deterioration in bone quality will also be examined. Finally, whether age-related loss of GAGs can



be rejuvenated via supplementation of GAGs in vivo will be determined. The successful completion of these aims



will: 1) provide a new concept for understanding age and/or disease-related bone fragility fractures from



ultrastructural origins; 2) facilitate development of new strategies in prediction (e.g. biomarkers for diagnosis) and



prevention (e.g. therapeutical treatments) of bone fragility fractures. These challenging research goals will be



achieved by a strong research team with complementary expertise in bone biomechanics (Wang) and



biochemistry and animal studies (Jiang), respectively.