The impact of age-related changes in osteoclast function on the skeleton (R01)
Ended Project Grant Awarded Last action
- Award ID
- R01AR077538
- Recipient
-
Mayo Clinic UEI Y2K4F9RPRRG7 Part of Mayo Clinic
- Awarding agency
-
National Insititue of Arthritis and Musculoskeletal and Skin Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $5,728,424
Award facts
- Assistance listing
- 93.846 Arthritis, Musculoskeletal and Skin Diseases Research
- Completion date
- Funding
-
- $5,232,832.00 Federal
- $495,592.00 Non-federal
- Place of performance
- Rochester, MN 55905, USA
Award details come from USAspending.gov.
Description
- Abstract
- Age-related bone loss puts individuals at risk for debilitating osteoporotic fractures. Current osteoporosis therapies primarily target bone-resorbing osteoclasts to prevent further bone loss; however, because of the coupling of osteoclasts and osteoblasts, these therapies are limited by a concomitant decrease in bone formation. Thus, new treatments are needed to reduce bone loss while protecting or stimulating new bone formation. Osteoclasts are multinucleated cells derived from the myeloid lineage. While most well-known for bone resorption, osteoclasts exhibit a range of functions, including stimulating bone formation by osteoblasts (coupling activity). Increasing evidence shows that osteoclasts exhibit functional heterogeneity. Our data presented herein confirm that not all osteoclasts are actively resorbing or coupling, and others have documented heterogeneity in osteoclast resorptive activity itself. With aging, there is a shift in osteoclast functional distribution, with an increase in the percentage of actively resorbing osteoclasts and a decrease in osteoclasts positive for coupling factor expression. Aging also leads to an increase in an aggressive subpopulation of osteoclasts, which move while resorbing bone leading to trench formation. Our data support that these aggressive, trench-forming osteoclasts, which exhibit greater acidification of the resorption lacunae and increased protease activity, have impaired ability to recruit osteoprogenitors to sites of resorption. Therefore, we hypothesize that the increase in aggressive, trench-forming osteoclasts with age is linked to reduced osteoclast coupling activity, leading to overall bone loss. To test this hypothesis, we propose to 1) determine whether inducible activation of osteoclast coupling activity prevents age-related bone loss.; 2) evaluate whether differential osteoclast resorptive behaviors impact coupling; and 3) test the role of matrix-derived TGF-SS as a feedback mechanism to modulate osteoclast activity. Altogether, these studies will reveal the distribution of osteoclast behaviors and how these are dysregulated during aging. In addition, understanding the mechanisms by which changes in resorption contribute to altered coupling activity will reveal potential new therapeutic targets for shifting osteoclast activities to treat osteoclast-mediated bone disease.
Transactions
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| Amendment | $495,592 | $0 | |
| Original award | $495,592 | $495,592 |
Show all 24
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Syddansk Universitet (University Of Southern Denmark) | $18,412 | |
| Regents Of The University Of Michigan | $28,439 | |
| Syddansk Universitet (University Of Southern Denmark) | $116,266 | |
| Regents Of The University Of Michigan | $37,952 | |
| Regents Of The University Of Michigan | $36,404 | |
| Syddansk Universitet (University Of Southern Denmark) | $151,926 | |
| Syddansk Universitet (University Of Southern Denmark) | $169,032 | |
| Regents Of The University Of Michigan | $35,546 |
Quick answers
Who received award R01AR077538?
R01AR077538 was awarded to Mayo Clinic by National Insititue of Arthritis and Musculoskeletal and Skin Diseases (National Institutes of Health) on June 15, 2021.
How much is award R01AR077538 worth?
$5,728,424 has been obligated on R01AR077538: $5,232,832 in federal funding and $495,592 in non-federal funding.
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