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A dual proteolytic axis regulates osteoclast-mediated bone coupling activity

Award Number: R01AR075168
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: 09/15/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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A dual proteolytic axis regulates osteoclast-mediated bone coupling activity - Abstract Skeletal homeostasis reflects a balanced state of bone remodeling, requiring a combination of osteoclast- dependent bone resorption and osteoblast-mediated bone formation. In turn, pathologic bone remodeling precipitates a variety of bone-destructive disease states, ranging from osteoporosis to rheumatoid arthritis. In addition to the traditional role of osteoclasts as bone eaters , these cells also participate in the maintenance of bone homeostasis via the release of signaling molecules that establish crosstalk with osteoblast-lineage cells. Despite advances in the field, however, the molecular mechanisms that allow osteoclasts to both degrade and induce new bone formation in a timely fashion remain to be defined. In new studies, we have found that cathepsin K (Ctsk)-null osteoclasts dramatically upregulate expression of the membrane-anchored matrix metalloproteinase, Mmp14/MT1-MMP, raising the possibility that, working together, the two proteinases play a previously unrecognized role in regulating osteoclast function. As such, we generated myeloid-specific Csf1r- Cre/Mmp14f/f/Ctskf/f mice where we find that the double knockout (DKO) mice unexpectedly display striking increases in bone mass and osteogenic coupling activity relative to myeloid-specific cathepsin K-null (CtskΔM/ΔM) or Mmp14-null (Mmp14ΔM/ΔM) mice. Further, the up-regulated bone formation parameters observed in these mice occur while leaving bone resorptive activity comparable to that found in CtskΔM/ΔM mice. In an effort to define the mechanisms underlying a combined requirement for Mmp14 and Ctsk in osteoclast-mediated bone coupling activity, the transcriptome of DKO osteoclasts reveals unexpected alterations in TGFβ receptor signaling in tandem with the decreased expression of the tetraspanin family member, Tspan4. These findings led us to posit a new model wherein Mmp14 and Ctsk co-regulate the TGFβ/Smad-dependent control of Tspan4 whose expression directs the formation of osteoclast migrasomes, a new type of organelle/extracellular vesicle deposited by migrating cells. Further, we provide supporting evidence that wild-type osteoclast-derived migrasomes negatively regulate skeletal stem/progenitor cell recruitment and osteoblastogenesis, thereby preventing premature or unrestrained bone formation. In turn, migrasome-deficient DKO osteoclasts create conditions permissive for excessive osteogenesis and bone formation. Given these preliminary findings, we propose to i) characterize the cooperative role played by a new Mmp14/Ctsk couplet in controlling osteoclast- mediated osteogenic bone coupling functions in vitro and in vivo, utilizing both myeloid- and osteoclast-specific conditional knockout mice; ii) define a novel Mmp14/Ctsk-TGF-β/Smad-Tspan4 axis that regulates osteoclast migrasome formation and bone coupling activity in vitro and in vivo, and iii) identify the osteoclast-derived migrasome component(s) that control osteoblastogenic recruitment and commitment of skeletal stem/progenitor cells. The proteolytic/bone coupling synergy outlined herein should provide new insights into bone remodeling while advancing the search for improved therapeutic interventions designed to prevent pathologic bone loss.


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: 2025 ( Subtotal = $332,904 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	7	6/11/2025	NON-COMPETING CONTINUATION	$332,904
2025	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	2/27/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $332,904

Issue Date FY: 2024 ( Subtotal = $343,200 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	8/13/2024	COMPETING CONTINUATION	$343,200
														Subtotal = $343,200

Issue Date FY: 2023 ( Subtotal = $343,200 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	6/23/2023	NON-COMPETING CONTINUATION	$343,200
														Subtotal = $343,200

Issue Date FY: 2022 ( Subtotal = $339,768 )
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	7/12/2022	NON-COMPETING CONTINUATION	$339,768
														Subtotal = $339,768

Issue Date FY: 2021 ( Subtotal = $332,904 )
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	6/7/2021	NON-COMPETING CONTINUATION	$332,904
2021	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	10/16/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $332,904

Issue Date FY: 2020 ( Subtotal = $343,200 )
2020	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/25/2020	NON-COMPETING CONTINUATION	$343,200
														Subtotal = $343,200

Issue Date FY: 2019 ( Subtotal = $343,200 )
2019	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/11/2019	NEW	$343,200
														Subtotal = $343,200

Grand Total All Awards = $2,378,376

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A dual proteolytic axis regulates osteoclast-mediated bone coupling activity

Award Number: R01AR075168

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: 09/15/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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