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Proteoglycans and age-related deterioration of bone toughness

Award Number: R01AR076190
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Proteoglycans and age-related deterioration of bone toughness - PROJECT SUMMARY Bone fragility fractures are a major concern of health care of our rapidly aging populations due to the high risk of long-term disability and even premature mortality. Such fractures are not only due to loss of bone mineral density (BMD), but also due to adverse composition/structural changes at different hierarchies of bone. It is a well-known fact that bone loses its toughness completely when dehydrated. However, the underlying mechanism is still elusive. Our preliminary results suggest that proteoglycans (PGs), a sub group of non-collagenous proteins (NCPs) in bone matrix, play a pivotal role in bone tissue toughness. In addition, our results also reveal that PGs in bone matrix decreases with aging with the associated deterioration of bone toughness. Moreover, our pilot study shows that accumulated non-enzymatic glycation decreases PGs and this decrease can be compensated by delivering GAGs to bone matrix by subdermal administration, thus improving the toughness of bone. To this end, we hypothesize that (1) PGs contain glycosaminoglycans (GAGs) that attract and retain bound water in bone matrix, thus regulating the in situ hydration status of bone matrix and subsequently imposing a significant effect on the toughness of bone. (2) Aging may cause loss of GAGs/PGs in bone matrix, thus leading to significant deterioration of bone toughness, whereas supplement of GAGs may deter such age-related deterioration of bone toughness. We proposed two specific aims to address the hypotheses. Aim 1: Determine the underlying mechanism of GAGs/PGs in toughening of bone. Here, we will use in vitro human cadaveric bone, in vivo mouse, and computational models to test the hypothesis in three subaims: (1) Determine the role of GAGs in retaining bound water in bone matrix using an in vitro model. (2) Determine the role of GAGs/PGs in toughening of bone in vivo using KO mouse models. (3) Verify the mechanistic role of GAGs in toughening bone using a computational approach. Aim 2: Determine the age-related loss in GAGs/PGs and its contribution to the age-related deterioration of bone toughness. Here, we will use ex vivo human cadaver bone and in vivo animal models to test the hypothesis in three subaims: (1) Determine age-related effect of GAGs/PGs on the toughness of cortical and trabecular bone for both genders using human cadaveric bone samples. (2) Determine the effect of nonenzymatic glycation on the synthesis of PGs by bone cells using a mouse bone ex vivo model and osteoblast cell models. (3) Determine the efficacy of supplemental GAGs in deterring age-related loss of GAGs and maintaining the toughness of bone using an aging rat model. Upon completion of this aim, we expect to understand the mechanistic role of GAGs/PGs in the age and gender-related deterioration of bone toughness, a potential pathway of age-related loss of GAGs, and the efficacy of supplementing GAGs in deterring age-related loss of bone toughness. The outcomes of this study will provide important insights to age-related bone fragility fractures and facilitate development of new strategies in prediction and prevention of fragility fractures in aged population.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = -$36,806 )
2026	2023	THE UNIVERSITY OF TEXAS AT SAN ANTONIO	1 UTSA CIR	SAN ANTONIO	TX	78249	BEXAR	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	2/25/2026	NON-COMPETING CONTINUATION	-$36,806
														Subtotal = -$36,806

Issue Date FY: 2023 ( Subtotal = $450,998 )
2023	2023	UNIVERSITY OF TEXAS AT SAN ANTONIO, THE	1 UTSA CIRCLE	SAN ANTONIO	TX	78249	BEXAR	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	6/12/2023	NON-COMPETING CONTINUATION	$450,998
														Subtotal = $450,998

Issue Date FY: 2022 ( Subtotal = $454,329 )
2022	2022	UNIVERSITY OF TEXAS AT SAN ANTONIO, THE	1 UTSA CIRCLE	SAN ANTONIO	TX	78249	BEXAR	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	6/13/2022	NON-COMPETING CONTINUATION	$454,329
														Subtotal = $454,329

Issue Date FY: 2021 ( Subtotal = $445,151 )
2021	2021	UNIVERSITY OF TEXAS AT SAN ANTONIO, THE	1 UTSA CIRCLE	SAN ANTONIO	TX	78249	BEXAR	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	6/4/2021	NON-COMPETING CONTINUATION	$445,151
														Subtotal = $445,151

Issue Date FY: 2020 ( Subtotal = $465,383 )
2020	2020	UNIVERSITY OF TEXAS AT SAN ANTONIO, THE	1 UTSA CIRCLE	SAN ANTONIO	TX	78249	BEXAR	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/8/2020	NON-COMPETING CONTINUATION	$465,383
														Subtotal = $465,383

Issue Date FY: 2019 ( Subtotal = $476,129 )
2019	2019	UNIVERSITY OF TEXAS AT SAN ANTONIO, THE	1 UTSA CIRCLE	SAN ANTONIO	TX	78249	BEXAR	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	6/28/2019	NEW	$480,911
2019	2019	UNIVERSITY OF TEXAS AT SAN ANTONIO, THE	1 UTSA CIRCLE	SAN ANTONIO	TX	78249	BEXAR	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	7/12/2019	NEW	-$4,782
														Subtotal = $476,129

Grand Total All Awards = $2,255,184

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Proteoglycans and age-related deterioration of bone toughness

Award Number: R01AR076190

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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