• BMNC
• inflammation
• macrophage
• osteoarthritis
• synovitis

• Disease-modifying OA drugs (DMOADs)
• Macrophage polarization
• Osteoarthritis
• Synovitis

• Cytokine
• Equine
• Immunomodulation
• Macrophage
• Monocyte

• Animals
• Horses
• Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology
• Granulocyte-Macrophage Colony-Stimulating Factor/metabolism
• Lipopolysaccharides/pharmacology
• Interleukin-10/metabolism
• Interleukin-4/metabolism
• Monocytes
• Macrophages/metabolism
• Cell Differentiation
• Interferon-gamma/metabolism
• Cells, Cultured

• KL2 TR002734 NCATS NIH HHS

Metformin is a widely accepted first-line hypoglycemic agent in current clinical practice, and it has been applied to the clinic for more than 60 years. Recently, researchers have identified that metformin not only has an efficient capacity to lower glucose but also exerts anti-aging effects by regulating intracellular signaling molecules. With the accelerating aging process and mankind’s desire for a long and healthy life, studies on aging have witnessed an unprecedented boom. Osteoporosis, sarcopenia, degenerative osteoarthropathy, and frailty are age-related diseases of the musculoskeletal system. The decline in motor function is a problem that many elderly people have to face, and in serious cases, they may even fail to self-care, and their quality of life will be seriously reduced. Therefore, exploring potential treatments to effectively prevent or delay the progression of aging-related diseases is essential to promote healthy aging. In this review, we first briefly describe the origin of metformin and the aging of the movement system, and next review the evidence associated with its ability to extend lifespan. Furthermore, we discuss the mechanisms related to the modulation of aging in the musculoskeletal system by metformin, mainly its contribution to bone homeostasis, muscle aging, and joint degeneration. Finally, we analyze the protective benefits of metformin in aging-related diseases of the musculoskeletal system.

• aging
• bone homeostasis
• drug effects
• metformin
• musculoskeletal diseases

Osteoarthritis (OA) may result from impaired ability of synovial macrophages to resolve joint inflammation. Increasing macrophage counts in inflamed joints through injection with bone marrow mononuclear cells (BMNC) induces lasting resolution of synovial inflammation. To uncover mechanisms by which BMNC may affect resolution, in this study, differential transcriptional signatures of BMNC in response to normal (SF) and inflamed synovial fluid (ISF) were analyzed. We demonstrate the temporal behavior of co-expressed gene networks associated with traits from related in vivo and in vitro studies. We also identified activated and inhibited signaling pathways and upstream regulators, further determining their protein expression in the synovium of inflamed joints treated with BMNC or DPBS controls. BMNC responded to ISF with an early pro-inflammatory response characterized by a short spike in the expression of a NF-ƙB- and mitogen-related gene network. This response was associated with sustained increased expression of two gene networks comprising known drivers of resolution (IL-10, IGF-1, PPARG, isoprenoid biosynthesis). These networks were common to SF and ISF, but more highly expressed in ISF. Most highly activated pathways in ISF included the mevalonate pathway and PPAR-γ signaling, with pro-resolving functional annotations that improve mitochondrial metabolism and deactivate NF-ƙB signaling. Lower expression of mevalonate kinase and phospho-PPARγ in synovium from inflamed joints treated with BMNC, and equivalent IL-1β staining between BMNC- and DPBS-treated joints, associates with accomplished resolution in BMNC-treated joints and emphasize the intricate balance of pro- and anti-inflammatory mechanisms required for resolution. Combined, our data suggest that BMNC-mediated resolution is characterized by constitutively expressed homeostatic mechanisms, whose expression are enhanced following inflammatory stimulus. These mechanisms translate into macrophage proliferation optimizing their capacity to counteract inflammatory damage and improving their general and mitochondrial metabolism to endure oxidative stress while driving tissue repair. Such effect is largely achieved through the synthesis of several lipids that mediate recovery of homeostasis. Our study reveals candidate mechanisms by which BMNC provide lasting improvement in patients with OA and suggests further investigation on the effects of PPAR-γ signaling enhancement for the treatment of arthritic conditions.

• arthritis
• joint therapy
• macrophage
• mevalonate pathway
• oxidative stress

• equine
• innate immunity
• macrophages
• osteoarthritis

• N/A Fulbright Scholar Program
• NCATS CTSA 5TL1TR002533-02 NIH HHS
• 5T32 OD010437 NIH HHS
• N/A Carolyn Quan and Porter Bennett

• RANK-RANKL system
• antiprogestin
• hormone-dependent diseases
• mesoprogestin
• osteoporosis

• Animals
• Biomarkers
• Bone and Bones/metabolism
• Disease Management
• Disease Susceptibility
• Drug Development
• Homeostasis
• Humans
• Osteogenesis/drug effects
• Osteoporosis/drug therapy
• Osteoporosis/etiology
• Osteoporosis/metabolism
• Osteoporosis/prevention & control
• Osteoprotegerin/chemistry
• Osteoprotegerin/pharmacology
• Osteoprotegerin/therapeutic use
• Protein Binding
• RANK Ligand
• Receptor Activator of Nuclear Factor-kappa B/metabolism
• Signal Transduction/drug effects

Osteoarthritis (OA) is the most prevalent joint disease causing major disability and medical expenditures. Synovitis is a central feature of OA and is primarily driven by macrophages. Synovial macrophages not only drive inflammation but also its resolution, through a coordinated, simultaneous expression of pro- and anti-inflammatory mechanisms that are essential to counteract damage and recover homeostasis. Current OA therapies are largely based on anti-inflammatory principles and therefore block pro-inflammatory mechanisms such as prostaglandin E₂ and Nuclear factor-kappa B signaling pathways. However, such mechanisms are also innately required for mounting a pro-resolving response, and their blockage often results in chronic low-grade inflammation. Following minor injury, macrophages shield the damaged area and drive tissue repair. If the damage is more extensive, macrophages incite inflammation recruiting more macrophages from the bone marrow to maximize tissue repair and ultimately resolve inflammation. However, sustained damage and inflammation often overwhelms pro-resolving mechanisms of synovial macrophages leading to the chronic inflammation and related tissue degeneration observed in OA. Recently, experimental and clinical studies have shown that joint injection with autologous bone marrow mononuclear cells replenishes inflamed joints with macrophage and hematopoietic progenitors, enhancing mechanisms of inflammation resolution, providing remarkable and long-lasting effects. Besides creating an ideal environment for resolution with high concentrations of interleukin-10 and anabolic growth factors, macrophage progenitors also have a direct role in tissue repair. Macrophages constitute a large part of the early granulation tissue, and further transdifferentiate from myeloid into a mesenchymal phenotype. These cells, characterized as fibrocytes, are essential for repairing osteochondral defects. Ongoing “omics” studies focused on identifying key drivers of macrophage-mediated resolution of joint inflammation and those required for efficient osteochondral repair, have the potential to uncover ways for developing engineered macrophages or off-the-shelf pro-resolving therapies that can benefit patients suffering from many types of arthropaties, not only OA.

• Osteoarthritis
• Arthropathy
• Synovitis
• Hematopoietic progenitor
• Homeostasis
• Cell therapy

• Bead-based assay
• Cytokine
• Flow cytometry
• Horse
• Inflammation

• Histomorphology
• Horse
• Metacarpophalangeal joint
• Synovial membrane
• Synoviocytes

Lameness due to musculoskeletal disease is the most common diagnosis in equine veterinary practice. Many of these orthopaedic disorders are chronic problems, for which no clinically satisfactory treatment exists. Thus, high hopes are pinned on regenerative medicine, which aims to replace or regenerate cells, tissues, or organs to restore or establish normal function. Some regenerative medicine therapies have already made their way into equine clinical practice mainly to treat tendon injures, tendinopathies, cartilage injuries and degenerative joint disorders with promising but diverse results. This review summarises the current knowledge of commonly used regenerative medicine treatments and critically discusses their use.

Musculoskeletal injuries and chronic degenerative diseases commonly affect both athletic and sedentary horses and can entail the end of their athletic careers. The ensuing repair processes frequently do not yield fully functional regeneration of the injured tissues but biomechanically inferior scar or replacement tissue, causing high reinjury rates, degenerative disease progression and chronic morbidity. Regenerative medicine is an emerging, rapidly evolving branch of translational medicine that aims to replace or regenerate cells, tissues, or organs to restore or establish normal function. It includes tissue engineering but also cell-based and cell-free stimulation of endogenous self-repair mechanisms. Some regenerative medicine therapies have made their way into equine clinical practice mainly to treat tendon injures, tendinopathies, cartilage injuries and degenerative joint disorders with promising results. However, the qualitative and quantitative spatiotemporal requirements for specific bioactive factors to trigger tissue regeneration in the injury response are still unknown, and consequently, therapeutic approaches and treatment results are diverse. To exploit the full potential of this burgeoning field of medicine, further research will be required and is ongoing. This review summarises the current knowledge of commonly used regenerative medicine treatments in equine patients and critically discusses their use.

• autologous conditioned serum
• equine
• horse
• musculoskeletal
• orthopaedic
• platelet-rich plasma
• regenerative medicine
• stem cell

• activation
• inflammatioin
• joint homeostasis
• osteoarthiritis
• polarization
• synovitis

• cell therapy
• homeostasis
• joint
• macrophage
• osteoarthritis