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Bone neuro-mechanosignaling and inflammation: New players in diabetic osteopenia

Award Number: R01AR073475
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Bone loss is a diabetic complication that is often overlooked and the underlying mechanisms are still not well understood. We have proposed that altered regulation of the osteocyte Panx1-P2X7R mechanosignaling complex disrupts proper load-induced bone adaptation and likely contributes to bone loss in Type 1 diabetes (T1D). However, load-induced regulation of bone mass occurs not only at the local bone level but remotely involving direct signaling between the bone and the nervous system. Diabetes affects the nervous system, particularly sensory nerves and yet, the extent to which diabetes impairs neural regulation of load-induced bone responses is still unknown. Our studies indicate that besides its role in osteocytic mechanosignaling, Panx1-P2X7R also participates in bone neuro-mechanosensory signaling and mediates load-induced inflammasome activation, two new functions that are also targeted by diabetes. Reduction in neurotrophic factors, mainly NGF, is a hallmark of diabetic peripheral neuropathy. NGF and its TrkA receptor are components of the bone neuro-mechanosensory system. Load-induced NGF release from osteoblast has been proposed to initiate NGF-TrkA signaling in bone sensory fibers that is essential for load-induced bone formation in mice. Our preliminary data indicates that NGF-TrkA signaling is attenuated in T1D Akita bones, as evidenced by lower NGF levels in bone and dorsal root ganglia (DRG) innervating the hind limbs. Moreover we observed that loading regulates expression of NGF-TrkA signaling components, a response that is lost in T1D bones. This finding suggests that diabetes disrupts the neurosensory axis of the bone mechanosensory system, thereby impairing the neural component of the load-induced regulation of bone formation. In addition, findings of load-induced Panx1-P2X7R upregulation in DRG suggest its participation in mechanisms that modulate bone sensory neurons excitability. Inflammation is associated with bone loss. Inflammatory cytokines are shown to be increased in bones at early stages of T1D in mice, which has been proposed to be necessary for induction of diabetic bone loss. Our preliminary data indicates that loading worsens inflammation in T1D Akita, which coincides with Panx1-P2X7R dysregulation and inflammasome activation. Load-induced flaring of inflammation in diabetic bone is likely driven by Panx1-P2X7R, known activators of NLRP3 inflammasome. Based on our preliminary data, we propose that (1) diabetic peripheral neuropathy contributes to the etiology of diabetic osteopenia by affecting the bone sensory fibers and altering neural regulation of load-induced bone formation; (2) Panx1-P2X7R regulation not only in the bone but also in the DRG is essential for load-induced responses and skeletal adaptation, and (3) load-induced dysregulation of Panx1-P2X7R in diabetic bone augments local inflammatory responses that contribute to impair bone anabolic responses. To test these hypotheses we will use T1D mouse models, insulin therapy, time series loading, molecular, biochemical, histomorphometric, pharmacological and genetic approaches. These studies will establish the importance of bone neuro-mechanosignaling and inflammation as new players in diabetic osteopenia and identify novel and critical roles for the Panx1-P2X7R functional complex in regulation of bone adaptation in health and disease.


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: 2022 ( Subtotal = $414,649 )
2022	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	8/5/2022	NON-COMPETING CONTINUATION	$37,697
2022	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	1/8/2022	NON-COMPETING CONTINUATION	$376,952
														Subtotal = $414,649

Issue Date FY: 2021 ( Subtotal = $406,270 )
2021	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	12/17/2020	NON-COMPETING CONTINUATION	$376,952
2021	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	6/8/2021	NON-COMPETING CONTINUATION	$29,318
														Subtotal = $406,270

Issue Date FY: 2020 ( Subtotal = $418,836 )
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	4/14/2020	NON-COMPETING CONTINUATION	$41,884
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	1/15/2020	NON-COMPETING CONTINUATION	$376,952
														Subtotal = $418,836

Issue Date FY: 2019 ( Subtotal = $418,836 )
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	3	2/15/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$418,836
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	005	3	4/4/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	12/5/2018	NON-COMPETING CONTINUATION	$418,836
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	007	3	4/8/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$134,241
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	004	2	4/3/2019	NON-COMPETING CONTINUATION	$0
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	2/15/2019	NON-COMPETING CONTINUATION	-$418,836
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	1	4/2/2019	NEW	$0
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	006	1	4/8/2019	NEW	-$134,241
														Subtotal = $418,836

Issue Date FY: 2018 ( Subtotal = $418,836 )
2018	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	2/16/2018	NEW	$418,836
														Subtotal = $418,836

Grand Total All Awards = $2,077,427

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Bone neuro-mechanosignaling and inflammation: New players in diabetic osteopenia

Award Number: R01AR073475

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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