Research on bone marrow aspirate concentrate knee cartilage repair

Marc Darrow, MD, JD.

The subject of knee cartilage mesenchymal stem cell repair has been the subject of diverse research over the years. Let’s start in 2011, (1) where doctors at the University of Aberdeen published research in the journal Arthritis and rheumatism that provided the first evidence that resident stem cells in the knee joint synovium underwent proliferation (multiplied) and chondrogenic differentiation (made themselves into cartilage cells) following injury. This paper, presenting the idea that stem cells in an injured knee increased in numbers in preparation of healing has been cited more than 200 times on google scholar.

One of these papers is a June 2019 study (2) in which researchers suggest that in both rheumatoid arthritis and degenerative arthritis, communication between the native cells in the damage knee causes an increase of stem cells found in the synovial fluid. A study in The journal of knee surgery,(3) May 2020 noted that synovial fluid-derived stem cell population increase exponentially in patients with joint injury or disease, pointing to a potential use as a biomarker or as a treatment of some orthopedic disorders.


Why doesn’t your knee fix itself


An October 2019 study from a French research team suggests why.(4)

In this first part of the research observations, the normal healing cycle is explored:

“The synovium exercises its main function in joint homeostasis (the balance of cells within the joint that allows it to repair itself) through the secretion of factors (such as lubricin (as its name suggests a natural lubricant that covers the knee cartilage) and hyaluronic acid) that are critical for the joint lubrication and function.

The main synovium cell components are fibroblast-like synoviocytes (cells that produce the proteins that create natural lubricants), mesenchymal stromal/stem cells and macrophage-like synovial cells (cells that help breakdown and dispose of damaged tissue). In the synovium, cells of mesenchymal origin modulate local inflammation and fibrosis (the regeneration and formation of connective tissue), and interact with different fibroblast subtypes and with resident macrophages.”

The problem in both osteoarthritis and rheumatoid arthritis is runaway inflammation:

“In pathologic conditions, such as rheumatoid arthritis, fibroblast-like synoviocytes proliferate abnormally . . The resulting synovial hyperplasia leads to secondary cartilage destruction, joint swelling, and pain.”

The swelling in your knee is a result in part to stem cells in your knees creating too much inflammation.


A theory behind stem cells is that they can reboot the abnormal cell activity (too much inflammation) through communication pathways with other cells.


A study from the University of Calgary posed the above question, if the stem cells in the knee synovial lining are abundant and have the ability to rebuild cartilage after injury, why isn’t the knee fixing itself? Here is what the researchers published, it has to do with communication.

“Since osteoarthritis leads to a progressive loss of cartilage and synovial progenitors (rebuilding) cells have the potential to contribute to articular cartilage repair, the inability of osteoarthritis synovial fluid Mesenchymal progenitor cells (stem cell growth factors) to spontaneously differentiate into chondrocytes suggests that cell-to-cell aggregation and/or communication may be impaired in osteoarthritis and somehow dampen the normal mechanism of chondrocyte replenishment from the synovium or synovial fluid. Should the cells of the synovium or synovial fluid be a reservoir of stem cells for normal articular cartilage maintenance and repair, these endogenous sources of chondro-biased cells would be a fundamental and new strategy for treating osteoarthritis and cartilage injury if this loss of aggregation & differentiation phenotype can be overcome.”(5)

In common terms, the “reservoir of stem cells for normal articular cartilage maintenance and repair,” already in the knee, are not fixing the knee because of a confused communication. The joint environment has changed from healing to degenerative.

The paper suggests getting these stem cells communicating and healing would create a fundamental new strategy in healing

This research was supported in a study from December 2017 In Nature reviews. The paper suggested that recognizing that joint-resident stem cells are comparatively abundant in the joint and occupy multiple niches (from the center of the joint to the out edges) will enable the optimization of single-stage therapeutic interventions for osteoarthritis.(6) The idea is to get these native stem cells to repair.


Researchers suggest that exploring how synovial fluid attracts cells to damage seems to be the way to find a potential treatment for cartilage degeneration.


In 2014, a study published in the journal Stem cell research & therapy (7) suggested that synovial fluid plays a role in attracting NATIVE stem cells to areas of damage within a synovial joint. This role is crucial for maintaining joint homeostasis. The researchers suggested that exploring how synovial fluid attracts stem cells to damage seems to be the way to find a potential treatment for cartilage degeneration.

Now we know that there are many stem cells in the knee, and, when there is damage to the knee, there are even more stem cells. If we can figure out how to get these stem cells turned on to the healing mode, the knee could heal itself of early stage osteoarthritis. So the problem is not the number of stem cells, there is a lot of them already in the knee, BUT, communication. Introduction of new stem cells with “fresh communication,” from the sideline may change that.

This failure of native stem cells to communicate the right healing instructions in a damaged knee was also seen in other research. In 2016, another heavily cited paper, noted that despite their larger numbers, the native stem cells act chaotically and are unable to regroup themselves into a healing mechanism and repair the bone, cartilage and other tissue. Introducing bone marrow stem cells into this environment gets the native stem cells in line and redirects them to perform healing functions. The joint environment is changed from chaotic to healing because of communication.(8) It should be pointed out that 62 medical studies cited the research in this paper’s findings.

A recent paper from a research team in Australia confirms how this change of joint environment works. It starts with cell signaling a new communication network is built.

  • When introduced into a diseased joint, stem cells display plasticity and multipotency (the ability to change/morph into other cell types, multiply. They also signal the native stem cells and other growth factors to regroup and begin repairing damaged joints.)
  • Mesenchymal stem cells express various growth factors – an array of bioactive molecules that stimulate local tissue repair – These growth factors, and the direct cell to cell contact between MSCs and chondrocytes (the present remaining cartilage cells in the joint), have been observed to influence chondrogenic differentiation and cartilage matrix formation – in simple terms – stem cells regenerated cartilage.(9)

Let’s look at a June 2021 paper: (10)

“Biological products are strongly supported by in vitro evidence but there is still a lack of robust clinical evidence. PRP and mesenchymal stem cells seem to relieve osteoarthritis symptoms through a regulation of the joint homeostasis, even if their capability to restore articular cartilage is still to be proved in vivo.”

University of Iowa research published in the Journal of orthopaedic research discusses meniscus injury and osteoarthritis development:

This is from that research: “Serious meniscus injuries seldom heal and increase the risk for knee osteoarthritis; thus, there is a need to develop new reparative therapies. In that regard, stimulating tissue regeneration by autologous (from you, not donated) stem/progenitor cells has emerged as a promising new strategy.

(The research team) showed previously that migratory chondrogenic progenitor cells (mobile cartilage growth factors) were recruited to injured cartilage, where they showed a capability in situ (on the spot) tissue repair. Here, we tested the hypothesis that the meniscus contains a similar population of regenerative cells.

Explant studies revealed that migrating cells were mainly confined to the red zone (where the blood is and its growth factors) in normal menisci: However, these cells were capable of repopulating defects made in the white zone (the “desert area” where no blood flows. Migrating cell numbers increased dramatically in damaged meniscus. Relative to non-migrating meniscus cells, migrating cells were more clonogenic, overexpressed progenitor cell markers, and included a larger side population. (They were ready to heal) Gene expression profiling showed that the migrating population was more similar to chondrogenic progenitor cells (mobile cartilage growth factors) than other meniscus cells. Finally, migrating cells equaled chondrogenic progenitor cells in chondrogenic potential, indicating a capacity for repair of the cartilaginous white zone of the meniscus. These findings demonstrate that, much as in articular cartilage, injuries to the meniscus mobilize an intrinsic progenitor cell population with strong reparative potential.”(11)


Summary

A May 2022 paper (12) concluded following a review of 723 patient histories that their “findings suggest that intra-articular injection of mesenchymal stem cells can reduce pain and enhance function in patients with knee osteoarthritis in a short period while also being relatively safe, even in the late stages of osteoarthritis of the knee. Although there is inadequate evidence to suggest that mesenchymal stem cells may heal cartilage abnormalities at this time, we (the researchers) have reason to believe that they protect cartilage and slow down the deterioration of articular cartilage.”

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References 

1 Kurth TB, Dell’accio F, Crouch V, Augello A, Sharpe PT, De Bari C. Functional mesenchymal stem cell niches in adult mouse knee joint synovium in vivo. Arthritis Rheum. 2011 May;63(5):1289-300. doi: 10.1002/art.30234.
2 Cai S, Ming B, Ye C, Lin S, Hu P, Tang J, Zheng F, Dong L. Similar Transition Processes in Synovial Fibroblasts from Rheumatoid Arthritis and Osteoarthritis: A Single-Cell Study. J Immunol Res. 2019 Jul 24;2019:4080735. doi: 10.1155/2019/4080735. PubMed PMID: 31428656; PubMed Central PMCID: PMC6681591.
3 Fang W, Sun Z, Chen X, Han B, Vangsness CT Jr. Synovial Fluid Mesenchymal Stem Cells for Knee Arthritis and Cartilage Defects: A Review of the Literature [published online ahead of print, 2020 May 13]. J Knee Surg. 2020;10.1055/s-0040-1710366. doi:10.1055/s-0040-1710366
4 Brondello JM, Djouad F, Jorgensen C. Where to Stand with Stromal Cells and Chronic Synovitis in Rheumatoid Arthritis? Cells. 2019 Oct 15;8(10):1257. doi: 10.3390/cells8101257. PMID: 31618926; PMCID: PMC6829866.
5 Krawetz RJ, Wu YE, Martin L, Rattner JB, Matyas JR, Hart DA. Synovial Fluid Progenitors Expressing CD90+ from Normal but Not Osteoarthritic Joints Undergo Chondrogenic Differentiation without Micro-Mass Culture. Kerkis I, ed. PLoS ONE. 2012;7(8):e43616. doi:10.1371/journal.pone.0043616.
6 McGonagle D, Baboolal TG, Jones E. Native joint-resident mesenchymal stem cells for cartilage repair in osteoarthritis. Nature Reviews Rheumatology. 2017 Dec;13(12):719.
7 de Sousa EB, Casado PL, Moura Neto V, Duarte ME, Aguiar DP. Synovial fluid and synovial membrane mesenchymal stem cells: latest discoveries and therapeutic perspectives. Stem Cell Res Ther. 2014 Oct 3;5(5):112. doi: 10.1186/scrt501. PMID: 25688673; PMCID: PMC4339206.
8 Davatchi F, et al. Mesenchymal stem cell therapy for knee osteoarthritis: 5 years follow-up of three patients. Int J Rheum Dis. 2016 Mar;19(3):219-25.
9 Freitag J, Bates D, Boyd R, Shah K, Barnard A, Huguenin L, Tenen A. Mesenchymal stem cell therapy in the treatment of osteoarthritis: reparative pathways, safety and efficacy – a review. BMC Musculoskelet Disord. 2016 May 26;17(1):230. doi: 10.1186/s12891-016-1085-9. Review.
10 Fusco G, Gambaro FM, Di Matteo B, Kon E. Injections in the osteoarthritic knee: a review of current treatment options. EFORT Open Reviews. 2021 Jun 28;6(6):501-9.
11 Seol D, Zhou C, Brouillette MJ, Song I, Yu Y, Choe HH, Lehman AD, Jang KW, Fredericks DC, Laughlin BJ, Martin JA. Characteristics of meniscus progenitor cells migrated from injured meniscus. Journal of Orthopaedic Research. 2017 Sep;35(9):1966-72.
12 Shoukrie SI, Venugopal S, Dhanoa RK, Selvaraj R, Selvamani TY, Zahra A, Malla J, Hamouda RK, Hamid PF, Selvamani TY, Hamid P. Safety and efficacy of injecting mesenchymal stem cells into a human knee joint to treat osteoarthritis: A systematic review. Cureus. 2022 May 8;14(5).

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