Bone and Osteoarthritis (Topics in Bone Biology, 4)

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But the human skeletal stem cell turned out to share few markers with its mouse counterpart. Instead, the researchers had to compare the gene expression profiles of the mouse skeletal stem cell with those of several human cell types found at the growing ends of developing human bone. Doing so, they were able to identify a cell population that made many of the same proteins as the mouse skeletal stem cell. They then worked backward to identify markers on the surface of the human cells that could be used to isolate and study them as a pure population.

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The researchers showed that the human skeletal stem cell they identified is both self-renewing and capable of making bone, cartilage and stroma progenitors. It is found at the end of developing bone, as well as in increased numbers near the site of healing fractures. Not only can it be isolated from fracture sites, it can also be generated by reprogramming human fat cells or induced pluripotent stem cells to assume a skeletal fate.

Intriguingly, the skeletal stem cell also provided a nurturing environment for the growth of human hematopoietic stem cells — or the cells in our bone marrow that give rise to our blood and immune system — without the need for additional growth factors found in serum. We found that the stromal population that arises from the skeletal stem cell can keep hematopoietic stem cells alive for two weeks without serum. By studying the differentiation potential of the human skeletal stem cell, the researchers were able to construct a family tree of stem cells to serve as a foundation for further studies into potential clinical applications.

Understanding the similarities and differences between the mouse and human skeletal stem cell may also unravel mysteries about skeletal formation and intrinsic properties that differentiate mouse and human skeletons. In particular, the researchers found that the human skeletal stem cell expresses genes active in the Wnt signaling pathway known to modulate bone formation, whereas the mouse skeletal stem cell does not. The ultimate goal of the researchers, however, is to find a way to use the human skeletal stem cell in the clinic. Longaker envisions a future in which arthroscopy — a minimally invasive procedure in which a tiny camera or surgical instruments, or both, are inserted into a joint to visualize and treat damaged cartilage — could include the injection of a skeletal stem cell specifically restricted to generate new cartilage, for example.

If we can use this stem cell for relatively noninvasive therapies, it could be a dream come true. The researchers have a pending patent for the isolation, derivation and use of human skeletal stem cells and their downstream progenitors. Stanford Medicine is leading the biomedical revolution in precision health, defining and developing the next generation of care that is proactive, predictive and precise. Preclinical and clinical data for the use of mesenchymal stem cells in articular cartilage tissue engineering. Expert Opin Biol Ther ; 12 : — Mesenchymal stem cell therapy for knee osteoarthritis.

Preliminary report of four patients. Int J Rheum Dis ; 14 : — Treatment of knee osteoarthritis with autologous mesenchymal stem cells: a pilot study. Transplantation ; 95 : — Mesenchymal stem cell injections improve symptoms of knee osteoarthritis. Arthroscopy ; 29 : — Knee joint preservation with combined neutralising high tibial osteotomy HTO and matrix-induced autologous chondrocyte implantation MACI in younger patients with medial knee osteoarthritis: a case series with prospective clinical and MRI follow-up over 5 years.

Knee ; 19 : — Treatment of posttraumatic and focal osteoarthritic cartilage defects of the knee with autologous polymer-based three-dimensional chondrocyte grafts: 2-year clinical results. Arthritis Res Ther ; 9 : R Treatment of focal degenerative cartilage defects with polymer-based autologous chondrocyte grafts: four-year clinical results. Arthritis Res Ther ; 11 : R Novel nano-composite multi-layered biomaterial for the treatment of multifocal degenerative cartilage lesions. Knee Surg Sports Traumatol Arthrosc ; 17 : — A cell-free scaffold-based cartilage repair provides improved function hyaline-like repair at one year.

Clin Orthop Relat Res ; : — OARSI recommendations for the management of hip and knee osteoarthritis, part I: critical appraisal of existing treatment guidelines and systematic review of current research evidence. American College of Rheumatology recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee.


Arthritis Care Res Hoboken 64 : — Acetaminophen toxicity in an urban county hospital. Black M. Acetaminophen hepatotoxicity. Annu Rev Med ; 35 : — US Food and Drug Administration. Silver Spring: FDA, Does paracetamol acetaminophen reduce the pain of osteoarthritis? A meta-analysis of randomised controlled trials.

Ann Rheum Dis ; 63 : — Acetaminophen for osteoarthritis. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 patients. BMJ ; : 15— Garcia RL , Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs.

Information for Healthcare Professionals: Valdecoxib marketed as Bextra. Trends in prescription of opioids from in persons with knee osteoarthritis. Arthritis Care Res Hoboken ; 66 : — Once-daily, controlled-release tramadol and sustained-release diclofenac relieve chronic pain due to osteoarthritis: a randomized controlled Trial. Pain Res Manag ; 13 : — Extended-release tramadol in the treatment of osteoarthritis: a multicenter, randomized, double-blind, placebo-controlled clinical trial.

Curr Med Res Opin ; 22 : — Am J Ther ; 18 : — A double-blind, randomized, placebo-controlled study of the efficacy and safety of duloxetine for the treatment of chronic pain due to osteoarthritis of the knee. Pain Pract ; 11 : 33— Duloxetine, a centrally acting analgesic, in the treatment of patients with osteoarthritis knee pain: a week, randomized, placebo-controlled trial. Pain ; : — Technology insight: adult mesenchymal stem cells for osteoarthritis therapy.

Nat Clin Pract Rheumatol ; 4 : — Off-label use of bone morphogenetic proteins in the United States using administrative data. Spine Phila Pa ; 35 : — Phase 1 Safety and tolerability study of BMP-7 in symptomatic knee osteoarthritis. BMC Musculoskelet Disord ; 11 : Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study.

Arthritis Rheum ; 61 : — A randomized, double-blind study of AMG a fully human monoclonal antibody to IL-1R1 in patients with osteoarthritis of the knee. Arthritis Res Ther ; 13 : R Tanezumab for the treatment of pain from osteoarthritis of the knee. Control of arthritis pain with anti-nerve-growth factor: risk and benefit.

Curr Rheumatol Rep ; 14 : — Intraarticular sprifermin recombinant human fibroblast growth factor 18 in knee osteoarthritis: a randomized, double-blind, placebo-controlled trial.


Arthritis Rheumatol ; 66 : — Intra-articular injection of an autologous preparation rich in growth factors for the treatment of knee oa: a retrospective cohort study. Clin Exp Rheumatol ; 26 : — Infiltration of plasma rich in growth factors for osteoarthritis of the knee short-term effects on function and quality of life.

Arch Orthop Trauma Surg ; : — Injection of platelet-rich plasma in patients with primary and secondary knee osteoarthritis: a pilot study. Am J Phys Med Rehabil ; 89 : — Platelet-rich plasma: intra-articular knee injections produced favorable results on degenerative cartilage lesions.

Knee Surg Sports Traumatol Arthrosc ; 18 : — A diketopiperazine fragment of human serum albumin modulates t-lymphocyte cytokine production through Rap1. J Trauma ; 64 : 35— A randomized clinical trial to evaluate two doses of an intra-articular injection of LMWF-5A in adults with pain due to osteoarthritis of the knee. Plos One ; 9 : e Ampio Pharmaceuticals Inc. Englewood: Ampio Pharmaceuticals Inc. Methotrexate for pain relief in knee osteoarthritis: an open-label study.

Rheumatology Oxford ; 52 : — Pain reduction with oral methotrexate in knee osteoarthritis, a pragmatic phase iii trial of treatment effectiveness PROMOTE : study protocol for a randomized controlled trial. Trials ; 16 : London: BioMed Central, Methotrexate in the treatment of symptomatic knee osteoarthritis: randomised placebo-controlled trial. Ann Rheum Dis Cell transplantation for articular cartilage defects: principles of past, present, and future practice.

Cell Transplant ; 20 : — Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. Tuan RS. A second-generation autologous chondrocyte implantation approach to the treatment of focal articular cartilage defects. Arthritis Res Ther ; 9 : Cartilage repair: generations of autologous chondrocyte transplantation. Eur J Radiol ; 57 : 24— Treatment of osteochondritis dissecans of the knee with autologous chondrocyte transplantation: results at two to ten years.

Two- to 9-year outcome after autologous chondrocyte transplantation of the knee. Clin Orthop Relat Res — Rockville: FDA, Autologous chondrocyte implantation compared with microfracture in the knee. A randomized trial. Osteoarthr Cartilage ; 15 : B11—B Surgical treatment for early osteoarthritis. Part I: cartilage repair procedures. Knee Surg Sports Traumatol Arthrosc ; 20 : — Repair of large chondral defects of the knee with autologous chondrocyte implantation in patients 45 years or older. Autologous chondrocyte implantation for joint preservation in patients with early osteoarthritis.

Donor site morbidity after articular cartilage repair procedures: a review. Acta Orthop Belg ; 76 : — Dedifferentiation-associated changes in morphology and gene expression in primary human articular chondrocytes in cell culture. Osteoarthritis Cartilage ; 10 : 62— Chondrogenic differentiation of cultured human mesenchymal stem cells from marrow.

Tissue Eng ; 4 : — Characterization and expression analysis of mesenchymal stem cells from human bone marrow and adipose tissue. Cell Physiol Biochem ; 14 : — Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum ; 44 : — Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis.

Review: tissue engineering for regeneration of articular cartilage. Biomaterials ; 21 : — New methods to diagnose and treat cartilage degeneration. Nat Rev Rheumatol ; 5 : — Matrix-associated autologous chondrocyte transplantation in a compartmentalized early stage of osteoarthritis.

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Osteoarthritis Cartilage ; 21 : — Getting arthritis gene therapy into the clinic. Nat Rev Rheumatol ; 7 : — US National Institutes of Health. Bethesda: ClinicalTrials. Initial phase I safety of retrovirally transduced human chondrocytes expressing transforming growth factor-beta-1 in degenerative arthritis patients. Cytotherapy ; 14 : — Osteoarthr Cartilage ; 20 : S27—S Activation of beta-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult beta-catenin conditional activation mice. J Bone Miner Res ; 24 : 12— Deletion of the transforming growth factor beta receptor type ii gene in articular chondrocytes leads to a progressive osteoarthritis-like phenotype in mice.

Arthritis Rheum ; 65 : — MMP13 is a critical target gene during the progression of osteoarthritis. Arthritis Res Ther ; 15 : R5. Biomaterials ; 35 : — Nat Med ; 15 : — Development of musculoskeletal toxicity without clear benefit after administration of PG, a matrix metalloproteinase inhibitor, to patients with knee osteoarthritis: a randomized, month, double-blind, placebo-controlled study. Inhibitory function of parathyroid hormone-related protein on chondrocyte hypertrophy: the implication for articular cartilage repair.

Arthritis Res Ther ; 14 : The promotion of osteochondral repair by combined intra-articular injection of parathyroid hormone-related protein and implantation of a bi-layer collagen-silk scaffold. Biomaterials ; 34 : — Regulation of rate of cartilage differentiation by indian hedgehog and PTH-related protein.

Science ; : — Teriparatide as a chondroregenerative therapy for injury-induced osteoarthritis. Sci Transl Med ; 3 : r—r. Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Blockade of the hedgehog pathway inhibits osteophyte formation in arthritis. Ann Rheum Dis ; 71 : — Inhibition of TGF-beta signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat Med ; 19 : — To Wnt or not to Wnt: the bone and joint health dilemma.

Nat Rev Rheumatol ; 9 : — Dkkmediated inhibition of Wnt signaling in bone ameliorates osteoarthritis in mice. Trounson A. The production and directed differentiation of human embryonic stem cells. Endocr Rev ; 27 : — This biomaterial-based membrane is also sutured over the defect and followed by cell suspension injected underneath. The advance in tissue engineering contributes tangibly to the third generation. Cultured chondrocytes are pre-seeded on a three-dimensional scaffold and trimmed to fit the defect size.

No periosteum or sutures are used in this method. MACI shows evident benefits over classic ACI as it reduces the surgical time, minimizes the fixation invasion and ensures even and long-term cell maintenance. The clinical outcomes of ACI have been well documented in full-thickness and osteochondral defect repair.

In , Brittberg et al. Eighty-eight percent of patients with femoral condylar defects showed good or excellent results after 2-year transplantation, but only Postoperative arthroscopy revealed 11 out of the 15 biopsies showing hyaline-like cartilage. Long-term follow-ups were subsequently reported by the same group for up to 10 years. Adverse effects were reported in 52 out of patients. Overall, ACI can be regarded as a reasonable treatment for deep cartilage defects.

The commercial product Carticel autologous cultured chondrocyte, manufacturer: Genzyme Biosurgery, Cambridge, MA, USA was initially approved by the FDA in for the repair of symptomatic cartilage defects of the femoral condyle caused by acute or repetitive trauma. OA cartilage, however, often affects the adjacent areas and disturbs the homeostasis of the whole joint cavity. In this degenerative microenvironment, the implanted chondrocytes may undergo undesired dedifferentiation or apoptosis, 97 , 98 therefore undermining efficacy.

At an average 5-year follow-up, treatment failure occurred in 12 knees that changed to joint arthroplasty. They concluded that ACI provided a plausible treatment for young OA patients and delayed the need for knee arthroplasty. Rosenberger et al. Three out of 32 OA patients were considered treatment failures. Their favorable findings pointed to consider classic ACI as a therapy for older age groups. Although no severe clinical safety issues have been associated with the ACI technique, there are still some problems including the limited cells available, multiple surgical procedures involved, in vitro chondrocyte dedifferentiation, and donor-site morbidity caused by cartilage harvest.

Bone Marrow Stem Cell Treatment (BMAC) for Knee Osteoarthritis - Mayo Clinic

In , Davatchi et al. After 1-year follow-up, pain produced during walking was reduced in three patients. The number of stairs to climb to produce pain and pain on a VAS were improved in all four patients. As the physical parameters improved slightly, the results were encouraging, but not ideal. In another trail, Orozco et al.

Cartilage quality was significantly improved in 11 of 12 patients as evidenced by T2 mapping quantification. They collected the cells from the infrapatellar fat pad and prepared these with PRP. Twenty-five patients with knee OA received this intra-articular injection. It yielded improved clinical outcomes on the 1-year follow-up as shown by the Lysholm, Tegner activity scale, and VAS scores; but no significant difference was detected between the MSC-treated group and the control group, which consisted of injections of PRP alone.

Magnetic resonance imaging MRI examination further confirmed the improvement in cartilage. However, no comparison between the treatment and control groups was shown. Overall, the preliminary results demonstrated that MSC-based therapy is encouraging in reducing pain and improving the function of OA. More RCTs with a large number of patients and long-term follow-up are needed before full-scale clinical translation. Tissue engineering involves the use of cells, scaffolds, and bioactive factors to enhance tissue mechanical properties and promote cell migration, attachment, proliferation, and differentiation to the desired cell type.

Tissue engineering therapy has shown a lot of promising outcomes in the treatment of cartilage defects. Treatment with cell-based scaffolds involves tissue harvest and cell expansion procedures that are used in ACI or other forms of cell therapy. The cells are pre-seeded on the scaffold, and the composite is subsequently implanted into the defect area with or without fixation. In a case series published by Bauer et al.

No major complications but minor complications were found including patellar tendinitis. In another clinical trial, 79 patients with posttraumatic and focal OA cartilage defects were treated with autologous chondrocyte-seeded BioSeed-C scaffold. Clinical assessment was performed in 40 patients with 2-year follow-ups. Histological results showed good integration of the graft and newly formed cartilaginous tissue. MRI analysis revealed that 16 out of 19 patients experienced moderate to complete filling of the defects.

These results showed that BioSeed-C is a potential therapeutic option for degenerative defects with stable effect. Although MACI technique has been reported with promising results for OA treatment in many trails, researchers demonstrated that MACI with Hyaff scaffold was questionable for knee OA due to the poor performance and high failure rate. They treated 44 patients using MACI as a salvage procedure. After a 9-year mean follow-up, Almost half This long-term follow-up study indicated that the tissue-engineered cartilage implantation should be fully investigated before its application as a salvage procedure for the treatment of OA.

Cell-free scaffolds are developed for one-stage procedure techniques, which can be either implanted alone to attract the endogenous cells or combined with biological products such as concentrated bone marrow or PRP. MRI analysis showed hyaline-like articular cartilage and non-visible subchondral oedema. The KOOS score was significantly increased, and histological staining revealed hyaline-like cartilage repair tissue at 1-year follow-up.

The above two pilot studies confirmed the usefulness of cell-free scaffolds. However, an in vivo study using sheep OA model demonstrated that cell-free approaches were inferior to MACI by macroscopic and histological examinations. Gene therapy enables the spatiotemporal control and persistent synthesis of gene products at target sites. Several preclinical studies have confirmed its safety and efficacy, and implicated its prospects, but few clinical trials have been conducted and no gene products have been approved for OA treatment.

Phase 1 and 2 trials have commenced, though results have not been published yet. Knee evaluation scores showed a dose-dependent improvement of symptoms. The placebo-controlled, double-blind, randomized phase 3 study was just completed on August but no study results have been posted as yet.

In this review, we presented the current progress of pharmacologic and regenerative therapy for OA treatment. The traditional OA drugs are effective in reducing pain and inflammation but insufficient to slow, stop, or reverse the joint damage, and are frequently associated with adverse effects. New OA drugs such as biologic agents and chemotherapeutic drugs show more marked effects and fewer side effects, and look more promising than traditional OA drugs.

Regenerative therapy is a novel strategy that has the potential to restore normal structure and function of damaged cartilage. At present, clinical studies in regenerative therapy are in its infancy with relatively rare and low-level evidence of success. Larger, random, controlled, and long-term follow-up studies are expected to take place in the coming years to confirm its safety and effectiveness. Although current pharmacologic and regenerative therapy show great promises, limitations still exist.

Potential therapies may be developed by exploring more therapeutic targets and methods. The emerging targets that have been confirmed in preclinical animal studies are also summarized in Table 2. As mentioned above, MMP13 and Adamts-5 are the main matrix-degrading enzymes that play a key role in the development of OA. In another study performed by Chen et al. In addition, Syndecan-4 was identified to control the activation of Adamts-5; therefore, the application of Syndecanspecific antibody could prevent proteoglycan loss and cartilage breakdown in a mouse OA model.

Current OA treatments aim to regenerate hyaline-like cartilage tissue. However, the repair tissue is often accompanied with undesirable chondrocyte hypertrophy and terminal differentiation, which cause matrix degradation and then impair the function of the repair tissue. Regarding cell therapy, pluripotent stem cells have unlimited self-renewal and chondrogenic differentiation capacity, offering an ideal cell source for cartilage repair and OA treatment compared with adult chondrocytes or MSCs.


Three chapters are dedicated to the classic topic of bone mechanics, which chapter dedicated to state-of-the-art advances in bone biology research. Mechanostat Hypothesis for Bones and Other Skeletal Organs (H M Frost) . osteogenesis imperfecta, Paget's disease, periodontitis, osteoarthritis and aseptic loosening. Topics in Bone Biology Offers a unique combination of information on the relationship of bone to the development of osteoarthritis price for Spain (gross).

Embryonic stem cells ESCs are pluripotent stem cells derived from early mammalian embryos. Induced pluripotent stem cells iPSCs are another type of pluripotent stem cells generated directly from adult cells. In terms of tissue-engineering strategies, more studies are now focusing on endogenous cell homing approaches. It aims at modifying a suitable microenvironment to recruit and mobilize the host cells from either the blood or a tissue-specific niche for self-repair.

It avoids the costs, complexity, and risks involved in in vitro cell expansion and reimplant procedure, and is therefore regarded as a cost-effective and technically simpler alternative to current cell transplantation. The key factors to a successful cell homing process are the favorable cell niche that can be enhanced by excellent bioscaffolds, signaling biomolecules, and release technology.

As OA usually affects complex tissues in the knee joint, this model may be exploited for future clinical treatment of OA disease. Zhang Y , Jordan JM. Epidemiology of osteoarthritis. Clin Geriatr Med ; 26 : — Felson DT. Clinical practice. N Engl J Med ; : — Osteoarthritis Cartilage ; 16 : — Hochberg MC , Dougados M. Pharmacological therapy of osteoarthritis. Best Pract Res Clin Rheumatol ; 15 : — Principles of Tissue Engineering. Basic science of articular cartilage and osteoarthritis. Clin Sports Med ; 24 : 1— Hunter W.

Of the structure and diseases of articulating cartilages, by William Hunter, Surgeon. Trans ; 42 : — Gilbert JE. Current treatment options for the restoration of articular cartilage.

Current research on pharmacologic and regenerative therapies for osteoarthritis

Am J Knee Surg ; 11 : 42— Hunziker EB. Articular cartilage repair: basic science and clinical progress. A review of the current status and prospects. Osteoarthritis Cartilage ; 10 : — The composition of normal and osteoarthritic articular cartilage from human knee joints. With special reference to unicompartmental replacement and osteotomy of the knee. J Bone Joint Surg Am ; 66 : 95— Venn M , Maroudas A.

Chemical composition and swelling of normal and osteoarthrotic femoral head cartilage. Chemical composition. Ann Rheum Dis ; 36 : — Sandell LJ , Aigner T. Articular cartilage and changes in arthritis. An introduction: cell biology of osteoarthritis. Arthritis Res ; 3 : — One flew over the progenitor's nest: migratory cells find a home in osteoarthritic cartilage. Cell Stem Cell ; 4 : — Cell death in osteoarthritis.

Curr Rheumatol Rep ; 10 : 37— Dreier R. Hypertrophic differentiation of chondrocytes in osteoarthritis: the developmental aspect of degenerative joint disorders. Arthritis Res Ther ; 12 : Osteoarthritis year in review: pathomechanisms. Osteoarthritis Cartilage ; 19 : — Articular cartilage calcification in osteoarthritis: insights into crystal-induced stress. Arthritis Rheum ; 63 : 10— Calcification of articular cartilage in human osteoarthritis.

Arthritis Rheum ; 60 : — Osteophytes: relevance and biology. Osteoarthritis Cartilage ; 15 : — Osteophytes and progression of knee osteoarthritis. Rheumatology Oxford ; 44 : — Characterization of articular cartilage and subchondral bone changes in the rat anterior cruciate ligament transection and meniscectomized models of osteoarthritis. Bone ; 38 : — Clinical trial of intra-articular injection of sodium hyaluronate in patients with osteoarthritis of the knee.

Curr Med Res Opin ; 11 : — Synovial tissue inflammation in early and late osteoarthritis.

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