Dr. Muhammad Farooq Rai

Early molecular detection of post-traumatic osteoarthritis

My laboratory investigates the basic and translational aspects of musculoskeletal research. The focus is on tissue injury, repair and degeneration (osteoarthritis). Using a population genetics approach, we have discovered certain mouse lines that have unusual abilities to repair ear and knee (articular) cartilage after injury and are protected from developing post-traumatic osteoarthritis. While phenotypic differences have been identified, it remains unknown how differential response in healing takes place at cell and gene level. The recent work on chondrocytes and stem cells as well as transcriptome profiling of various knee joint tissues in the healer and non-healer mouse lines unraveled cell and transcript level cues as to why some individuals can repair their damaged or loss tissues and are protected from osteoarthritis while others cannot repair their injured tissues and are susceptible to osteoarthritis.

Osteoarthritis affects 3-4% of human population and is one of the leading causes of disability. At least 12% of osteoarthritis is due to trauma to knee and is the focus of my research. The studies on post-traumatic osteoarthritis have been undertaken with the overall goal to underpinning of molecular changes immediately after the injury but before the onset of clinical disease characterized by cartilage fibrillation and loss, synovitis and narrowing of joint space width. This approach of understanding the disease before the clinical manifestations is of paramount significance in translational medicine as one of the main reasons why no effective therapy is available for osteoarthritis is the lack of understanding of the early (molecular) changes in the knee which occur 10-15 years before clinical disease and diagnosis.

Currently osteoarthritis is diagnosed at the end stage where no therapy is possible and surgical joint arthroplasty is the only answer. Thus, if we can move the focus from end-stage disease to early molecular detection, we can better understand the disease process and can identify a window of opportunity for devising new therapeutic candidates as well as new therapeutic targets. To this end, using RNA sequencing we have probed the transcriptomic landscape of cartilage, meniscus and ligaments in patients with knee injury and have identified novel therapeutic targets. Moreover, to gain mechanistic insights into the tissue injury and osteoarthritis, we have developed surgical (invasive) and mechanical (non-invasive) mouse models of meniscus and ligament injuries. These animal models allowed us to study the course of post-traumatic osteoarthritis and to test various therapeutic regimens.

Nanoparticle-RNAi targeting periostin for the treatment of osteoarthritis

Matricellular and matrix proteins, in particular periostin (Postn), are emerging as promising pharmacological targets for osteoarthritis. Postn is a secretory matricellular protein that plays a critical role in tissue development, repair, and disease, but little is known about its function in synovial joints. While we have strong evidence that Postn plays a critical role in the early stages of osteoarthritis, understanding the therapeutic potential of modulating Postn across the spectrum of age and disease severity, as well as elucidating the mechanisms of Postn effects, is essential to design and implement mechanism-based clinical interventions.

Mechanistically, we reported that suppressing Postn dampens the inflammatory NF-kB/MMP-13 signaling axis in mice after destabilization of medial meniscus and in human chondrocytes in response to IL-1β, suggesting that Postn displays inflammatory properties. Yet the underlying mechanistic details of Postn-related OA effects remain obscure, and the interplay between intracellular inflammatory cascade and Postn was not fully elucidated by these earlier studies. To this end, we have established that (a) activation of NF-kB classical kinase (IKK2) and expression of its downstream inflammatory signature IkBz are essential for osteoarthritis development, and (b) IkBz is a potentially critical player in the inflammatory response and osteoarthritis cartilage degradation, suggesting that IkBz may be a superior therapeutic target due to its inflammatory gene signature. We anticipate that these studies will yield novel mechanistic insights regarding the role of Postn in osteoarthritis and demonstrate the strong translational potential of Postn as a therapeutic target for osteoarthritis.

Selected Publications

1. Rai MF, Cai L, Zhang Q, Townsend RR, Brophy RH. Synovial fluid proteomics from serial aspirations of ACL injured knees identifies candidate biomarkers. Am J Sports Med 51(7):1733-1742 2023
2. Arra M, Swarnkar G, Adapala NS, Naqvi SK, Cai L, Rai MF, Singamaneni S, Mbalaviele G, Brophy R, Abu-Amer Y. Glutamine metabolism modulates chondrocyte inflammatory response. Elife 2022 11:e80725.
3. Yan M, Duan X, Cai L, Zhang W, Silva MJ, Brophy RH, Rai MF. KIF26B silencing prevents osseous transdifferentiation of progenitor/stem cells and attenuates ectopic calcification in a murine model. J Bone Miner Res 2022 37(2):349−368.
4. Duan X, Cai L, Pham CTN, Abu-Amer Y, Pan H, Brophy RH, Wickline SA, Rai MF. Amelioration of posttraumatic osteoarthritis in mice using intraarticular silencing of periostin via nanoparticle-based small interfering RNA. Arthritis Rheumatol 2021 73(12):2249−2260.
5. Attur M, Duan X, Cai L, Han T, Zhang W, Tycksen ED, Samuels J, Brophy RH, Abramson SB, Rai MF. Periostin loss-of-function protects mice from post-traumatic and age-related osteoarthritis. Arthritis Res Ther2021 23(1):104.
6. Arra M, Swarnkar G, Ke K, Otero JE, Ying J, Duan X, Maruyama T, Rai MF, O'Keefe RJ, Mbalaviele G, Shen J, Abu-Amer Y. LDHA-mediated ROS generation in chondrocytes is a potential therapeutic target for osteoarthritis. Nat Commun 2020 11(1):3427.
7. Rai MF, Cheverud JM, Schmidt EJ, Sandell LJ. Genetic correlations between cartilage regeneration and degeneration reveal an inverse relationship. Osteoarthritis Cartilage 2020 (28(8):1111−1120.
8. Duan X, Cai L, Schmidt EJ, Shen J, Tycksen ED, O'Keefe RJ, Cheverud JM, Rai MF. RNA-seq analysis of chondrocyte transcriptome reveals genetic heterogeneity in LG/J and SM/J murine strains. Osteoarthritis Cartilage 2020 28(4):516−527.
9. Brophy RH, Cai L, Duan X, Zhang Q, Townsend RR, Nunley RM, Guilak F, Rai MF. Proteomic analysis of synovial fluid identifies periostin as a biomarker for anterior cruciate ligament injury. Osteoarthritis Cartilage 2019 27(12):1778−1789.
10. Cai L, Brophy RH, Tycksen ED, Duan X, Nunley RM, Rai MF. Distinct expression pattern of periostin splice variants in chondrocytes and ligament progenitor cells. FASEB J 2019 33(7):8386−8405.
11. Yan H, Duan X, Pan H, Akk A, Sandell LJ, Wickline SA, Rai MF, Pham CTN. Development of a peptide-siRNA nanocomplex targeting NF-κB for efficient cartilage delivery. Sci Rep 2019 9(1):442.
12. Chinzei N, Rai MF, Hashimoto S, Schmidt EJ, Takebe K, Cheverud JM, Sandell LJ. Evidence for genetic contribution to variation in posttraumatic osteoarthritis in mice. Arthritis Rheumatol 2019 71(3):370−381.
13. Rai MF, Sandell LJ, Barrack TN, Cai L, Tycksen ED, Tang SY, Silva MJ, Barrack RL. A microarray study of articular cartilage in relation to obesity and severity of osteoarthritis. Cartilage 2018 11(4):458−472.
14. Zhang Y, Xiong C, Kudelko M, Li Y, Wang C, Wong YL, Tam V, Rai MF, Cheverud J, Lawson HA, Sandell L, Chan WCW, Cheah KSE, Sham PC, Chan D. Early onset of disc degeneration in SM/J mice is associated with changes in ion transport systems and fibrotic events. Matrix Biol 2018 70:123−139.
15. Chinzei N, Brophy RH, Duan X, Cai L, Nunley RM, Sandell LJ, Rai MF. Molecular influence of anterior cruciate ligament tear remnants on chondrocytes: a biologic connection between injury and osteoarthritis. Osteoarthritis Cartilage 2018 26(4):588−599.
16. Duan X, Sandell LJ, Chinzei N, Holguin N, Silva MJ, Schiavinato A, Rai MF. Therapeutic efficacy of intra-articular hyaluronan derivative and platelet-rich plasma in mice following axial tibial loading. PLoS One 201712(4):e0175682.
17. Rai MF, Duan X, Quirk JD, Holguin N, Schmidt EJ, Chinzei N, Silva MJ, Sandell LJ. Post-traumatic osteoarthritis in mice following mechanical injury to the synovial joint. Sci Rep 2017 7:45223.
18. Yan H, Duan X, Pan H, Holguin N, Rai MF, Akk A, Springer LE, Wickline SA, Sandell LJ, Pham CT. Suppression of NF-kB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury. Proc Natl Acad Sci USA 2016 113:E6199−E6208.
19. Rai MF, Sandell LJ, Zhang B, Wright RW, Brophy RH. RNA microarray analysis of macroscopically normal articular cartilage from knees undergoing partial medial meniscectomy: Potential prediction of the risk for developing osteoarthritis. PLoS One 2016 11:e0155373.
20. Rai MF, Patra D, Sandell LJ, Brophy RH. Relationship of gene expression in the injured human meniscus to body mass index: A biologic connection between obesity and osteoarthritis. Arthritis Rheumatol 201466:2152−2164
21. Hashimoto S, Rai MF, Gill CS, Zhang Z, Sandell LJ, Clohisy JC. Molecular characterization of articular cartilage from young adults with femoral acetabular impingement. J Bone Joint Surg (Am.) 2013 95:1457−1464.
22. Rai MF, Patra D, Sandell LJ, Brophy RH. Transcriptome analysis of human injured meniscus reveals a distinct phenotype of meniscus degeneration with aging. Arthritis Rheumatol 2013 65:2090−2101.
23. Rai MF, Hashimoto S, Johnson EE, Janiszak KL, Fitzgerald J, Heber-Katz E, Cheverud JM, Sandell LJ. Heritability of articular cartilage regeneration and its association with ear wound healing in mice. Arthritis Rheumatol 2012 64:2300–2310.
24. Rai MF, Graeve T, Twardziok S, Schmidt MFG. Evidence for regulated interleukin-4 expression in chondrocyte-scaffolds under in vitro inflammatory conditions. PLoS One 2011 6:e25749.
25. Rachakonda PS, Rai MF, Schmidt MFG. Application of inflammation-responsive promoter for an in vitro arthritis model. Arthritis Rheumatol 2008 58:2088–2097.