BMP signalling: A significant player and therapeutic target for osteoarthritis

Akrit Pran Jaswal; Bhupendra Kumar; Anke J Roelofs; Sayeda Fauzia Iqbal; Amaresh Kumar Singh; Anna H K Riemen; Hui Wang; Sadaf Ashraf; Sanap Vaibhav Nanasaheb; Nitin Agnihotri; Cosimo De Bari; Amitabha Bandyopadhyay

doi:10.1016/j.joca.2023.05.016

BMP signalling: A significant player and therapeutic target for osteoarthritis

Akrit Pran Jaswal
, Bhupendra Kumar
, Anke J Roelofs
, Sayeda Fauzia Iqbal
, Amaresh Kumar Singh
, Anna H K Riemen
, Hui Wang
, Sadaf Ashraf
, Sanap Vaibhav Nanasaheb
, Nitin Agnihotri
, Cosimo De Bari
, Amitabha Bandyopadhyay^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

11 Downloads (Pure)

Abstract

OBJECTIVE: To explore the significance of BMP signaling in osteoarthritis (OA) etiology, and thereafter propose a disease-modifying therapy for OA.

METHODS: To examine the role of the BMP signaling in pathogenesis of OA, an Anterior Cruciate Ligament Transection (ACLT) surgery was performed to incite OA in C57BL/6J mouse line at postnatal day 120 (P120). Thereafter, to investigate whether activation of BMP signaling is necessary and sufficient to induce OA, we have used conditional gain- and loss-of-function mouse lines in which BMP signaling can be activated or depleted, respectively, upon intraperitoneal injection of tamoxifen. Finally, we locally inhibited BMP signaling through intra-articular injection of LDN-193189 pre- and post-onset surgically induced OA. The majority of the investigation has been conducted using micro-CT, histological staining, and immuno histochemistry to assess the disease etiology.

RESULTS: Upon induction of OA, depletion of SMURF1-an intra-cellular BMP signaling inhibitor in articular cartilage coincided with the activation of BMP signaling, as measured by pSMAD1/5/9 expression. In mouse articular cartilage, the BMP gain-of-function mutation is sufficient to induce OA even without surgery. Further, genetic, or pharmacological BMP signaling suppression also prevented pathogenesis of OA. Interestingly, inflammatory indicators were also significantly reduced upon LDN-193189 intra-articular injection which inhibited BMP signaling and slowed OA progression post onset.

CONCLUSION: Our findings showed that BMP signaling is crucial to the etiology of OA and inhibiting BMP signaling locally can be a potent strategy for alleviating OA.

Original language	English
Pages (from-to)	1454-1468
Number of pages	15
Journal	Osteoarthritis and Cartilage
Volume	31
Issue number	11
Early online date	29 Jun 2023
DOIs	https://doi.org/10.1016/j.joca.2023.05.016
Publication status	Published - Nov 2023

Bibliographical note

Acknowledgements
We are immensely grateful to Prof. YiPing Chen at Tulane University, USA, for the gift of mouse strains. We thank Prof. Frank Beier of Western University, Ontario, Canada for teaching APJ the method of ACL transection. We sincerely thank Shuchi Arora and Ankita Jena for their critical comments on the manuscript. We are highly grateful to Niveda Udaykumar and Saahiba Thaleshwari for their help in blind OARSI scoring. We thank Mr. Naresh Gupta for assistance with mouse experiments.
Funding
This work was supported by grants from the Department of Biotechnology, India (DBT) BT/PR17362/MED/30/1648/2017 and BT/IN/DENMARK/08/JD/2016 to A.B.; Versus Arthritis Grants 19667 and 21156 to CDB and AJR, Fellowships to APJ, BK, and SFI are supported by fellowships from the Ministry of Education, Govt. of India. Fellowship to AKS was supported by Science and Engineering Research Board, Govt. of India. APJ travelled to Western University Canada with Shastri Research Student Fellowship (SRSF, 2015-‘16). A.H.K.R. was supported by the Wellcome Trust through the Scottish Translational Medicine and Therapeutics Initiative (Grant No. WT 085664).

Keywords

BMP
Osteoarthritis
articular cartilage
local inhibition
LDN-193189

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Cite this

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title = "BMP signalling: A significant player and therapeutic target for osteoarthritis",

abstract = "OBJECTIVE: To explore the significance of BMP signaling in osteoarthritis (OA) etiology, and thereafter propose a disease-modifying therapy for OA.METHODS: To examine the role of the BMP signaling in pathogenesis of OA, an Anterior Cruciate Ligament Transection (ACLT) surgery was performed to incite OA in C57BL/6J mouse line at postnatal day 120 (P120). Thereafter, to investigate whether activation of BMP signaling is necessary and sufficient to induce OA, we have used conditional gain- and loss-of-function mouse lines in which BMP signaling can be activated or depleted, respectively, upon intraperitoneal injection of tamoxifen. Finally, we locally inhibited BMP signaling through intra-articular injection of LDN-193189 pre- and post-onset surgically induced OA. The majority of the investigation has been conducted using micro-CT, histological staining, and immuno histochemistry to assess the disease etiology.RESULTS: Upon induction of OA, depletion of SMURF1-an intra-cellular BMP signaling inhibitor in articular cartilage coincided with the activation of BMP signaling, as measured by pSMAD1/5/9 expression. In mouse articular cartilage, the BMP gain-of-function mutation is sufficient to induce OA even without surgery. Further, genetic, or pharmacological BMP signaling suppression also prevented pathogenesis of OA. Interestingly, inflammatory indicators were also significantly reduced upon LDN-193189 intra-articular injection which inhibited BMP signaling and slowed OA progression post onset.CONCLUSION: Our findings showed that BMP signaling is crucial to the etiology of OA and inhibiting BMP signaling locally can be a potent strategy for alleviating OA.",

keywords = "BMP, Osteoarthritis, articular cartilage, local inhibition, LDN-193189",

author = "Jaswal, \{Akrit Pran\} and Bhupendra Kumar and Roelofs, \{Anke J\} and Iqbal, \{Sayeda Fauzia\} and Singh, \{Amaresh Kumar\} and Riemen, \{Anna H K\} and Hui Wang and Sadaf Ashraf and Nanasaheb, \{Sanap Vaibhav\} and Nitin Agnihotri and \{De Bari\}, Cosimo and Amitabha Bandyopadhyay",

note = "Acknowledgements We are immensely grateful to Prof. YiPing Chen at Tulane University, USA, for the gift of mouse strains. We thank Prof. Frank Beier of Western University, Ontario, Canada for teaching APJ the method of ACL transection. We sincerely thank Shuchi Arora and Ankita Jena for their critical comments on the manuscript. We are highly grateful to Niveda Udaykumar and Saahiba Thaleshwari for their help in blind OARSI scoring. We thank Mr. Naresh Gupta for assistance with mouse experiments. Funding This work was supported by grants from the Department of Biotechnology, India (DBT) BT/PR17362/MED/30/1648/2017 and BT/IN/DENMARK/08/JD/2016 to A.B.; Versus Arthritis Grants 19667 and 21156 to CDB and AJR, Fellowships to APJ, BK, and SFI are supported by fellowships from the Ministry of Education, Govt. of India. Fellowship to AKS was supported by Science and Engineering Research Board, Govt. of India. APJ travelled to Western University Canada with Shastri Research Student Fellowship (SRSF, 2015-{\textquoteleft}16). A.H.K.R. was supported by the Wellcome Trust through the Scottish Translational Medicine and Therapeutics Initiative (Grant No. WT 085664).",

year = "2023",

month = nov,

doi = "10.1016/j.joca.2023.05.016",

language = "English",

volume = "31",

pages = "1454--1468",

journal = "Osteoarthritis and Cartilage",

issn = "1063-4584",

publisher = "W.B. Saunders Ltd",

number = "11",

}

TY - JOUR

T1 - BMP signalling

T2 - A significant player and therapeutic target for osteoarthritis

AU - Jaswal, Akrit Pran

AU - Kumar, Bhupendra

AU - Roelofs, Anke J

AU - Iqbal, Sayeda Fauzia

AU - Singh, Amaresh Kumar

AU - Riemen, Anna H K

AU - Wang, Hui

AU - Ashraf, Sadaf

AU - Nanasaheb, Sanap Vaibhav

AU - Agnihotri, Nitin

AU - De Bari, Cosimo

AU - Bandyopadhyay, Amitabha

N1 - Acknowledgements We are immensely grateful to Prof. YiPing Chen at Tulane University, USA, for the gift of mouse strains. We thank Prof. Frank Beier of Western University, Ontario, Canada for teaching APJ the method of ACL transection. We sincerely thank Shuchi Arora and Ankita Jena for their critical comments on the manuscript. We are highly grateful to Niveda Udaykumar and Saahiba Thaleshwari for their help in blind OARSI scoring. We thank Mr. Naresh Gupta for assistance with mouse experiments. Funding This work was supported by grants from the Department of Biotechnology, India (DBT) BT/PR17362/MED/30/1648/2017 and BT/IN/DENMARK/08/JD/2016 to A.B.; Versus Arthritis Grants 19667 and 21156 to CDB and AJR, Fellowships to APJ, BK, and SFI are supported by fellowships from the Ministry of Education, Govt. of India. Fellowship to AKS was supported by Science and Engineering Research Board, Govt. of India. APJ travelled to Western University Canada with Shastri Research Student Fellowship (SRSF, 2015-‘16). A.H.K.R. was supported by the Wellcome Trust through the Scottish Translational Medicine and Therapeutics Initiative (Grant No. WT 085664).

PY - 2023/11

Y1 - 2023/11

N2 - OBJECTIVE: To explore the significance of BMP signaling in osteoarthritis (OA) etiology, and thereafter propose a disease-modifying therapy for OA.METHODS: To examine the role of the BMP signaling in pathogenesis of OA, an Anterior Cruciate Ligament Transection (ACLT) surgery was performed to incite OA in C57BL/6J mouse line at postnatal day 120 (P120). Thereafter, to investigate whether activation of BMP signaling is necessary and sufficient to induce OA, we have used conditional gain- and loss-of-function mouse lines in which BMP signaling can be activated or depleted, respectively, upon intraperitoneal injection of tamoxifen. Finally, we locally inhibited BMP signaling through intra-articular injection of LDN-193189 pre- and post-onset surgically induced OA. The majority of the investigation has been conducted using micro-CT, histological staining, and immuno histochemistry to assess the disease etiology.RESULTS: Upon induction of OA, depletion of SMURF1-an intra-cellular BMP signaling inhibitor in articular cartilage coincided with the activation of BMP signaling, as measured by pSMAD1/5/9 expression. In mouse articular cartilage, the BMP gain-of-function mutation is sufficient to induce OA even without surgery. Further, genetic, or pharmacological BMP signaling suppression also prevented pathogenesis of OA. Interestingly, inflammatory indicators were also significantly reduced upon LDN-193189 intra-articular injection which inhibited BMP signaling and slowed OA progression post onset.CONCLUSION: Our findings showed that BMP signaling is crucial to the etiology of OA and inhibiting BMP signaling locally can be a potent strategy for alleviating OA.

AB - OBJECTIVE: To explore the significance of BMP signaling in osteoarthritis (OA) etiology, and thereafter propose a disease-modifying therapy for OA.METHODS: To examine the role of the BMP signaling in pathogenesis of OA, an Anterior Cruciate Ligament Transection (ACLT) surgery was performed to incite OA in C57BL/6J mouse line at postnatal day 120 (P120). Thereafter, to investigate whether activation of BMP signaling is necessary and sufficient to induce OA, we have used conditional gain- and loss-of-function mouse lines in which BMP signaling can be activated or depleted, respectively, upon intraperitoneal injection of tamoxifen. Finally, we locally inhibited BMP signaling through intra-articular injection of LDN-193189 pre- and post-onset surgically induced OA. The majority of the investigation has been conducted using micro-CT, histological staining, and immuno histochemistry to assess the disease etiology.RESULTS: Upon induction of OA, depletion of SMURF1-an intra-cellular BMP signaling inhibitor in articular cartilage coincided with the activation of BMP signaling, as measured by pSMAD1/5/9 expression. In mouse articular cartilage, the BMP gain-of-function mutation is sufficient to induce OA even without surgery. Further, genetic, or pharmacological BMP signaling suppression also prevented pathogenesis of OA. Interestingly, inflammatory indicators were also significantly reduced upon LDN-193189 intra-articular injection which inhibited BMP signaling and slowed OA progression post onset.CONCLUSION: Our findings showed that BMP signaling is crucial to the etiology of OA and inhibiting BMP signaling locally can be a potent strategy for alleviating OA.

KW - BMP

KW - Osteoarthritis

KW - articular cartilage

KW - local inhibition

KW - LDN-193189

UR - https://www.scopus.com/pages/publications/85165723327

U2 - 10.1016/j.joca.2023.05.016

DO - 10.1016/j.joca.2023.05.016

M3 - Article

C2 - 37392862

SN - 1063-4584

VL - 31

SP - 1454

EP - 1468

JO - Osteoarthritis and Cartilage

JF - Osteoarthritis and Cartilage

IS - 11

ER -

BMP signalling: A significant player and therapeutic target for osteoarthritis

Abstract

Bibliographical note

Keywords

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