What’s New in Musculoskeletal Basic Science

Fundamental knowledge of the biology of the musculoskeletal system serves as a foundation for almost all clinical decisions made by orthopaedic surgeons during their professional careers. Therefore, it is of utmost importance for orthopaedic surgeons to learn about new biological developments as they may affect our clinical decision-making process. Although information overload on social media and the internet has made it more difficult to filter through the evidence, this update on the basic science is meant to highlight outstanding contributions to our understanding of the biology of bone and cartilage, spine physiology, osteoarthritis, and soft tissues, including tendons and ligaments. Basic science breakthroughs in musculoskeletal oncology will not be covered herein, as they are part of a separate update within The Journal of Bone & Joint Surgery. Spine Discectomies are one of the most commonly performed spine procedures and often result in immediate pain relief. However, there is a relatively high recurrence rate, likely due to incomplete healing of the anulus fibrosus defect caused by the initial herniation or by the surgical approach. Torre et al. recently investigated the cellular mechanisms associated with neonatal anulus fibrosus regeneration1. Although the adult mouse anulus fibrosus, similar to the human anulus fibrosus, scars in response to injury, the neonatal anulus fibrosus exhibits regenerative capacity. Using cell lineage tracing, the authors identified Scleraxis-lineage cells as the main contributors to anulus fibrosus regeneration. In the neonatal anulus fibrosus, Scleraxis-lineage cells lose their Scleraxis expression after injury, indicating dedifferentiation into a stem or progenitor cell type. These cells then proliferate and redifferentiate into Scleraxis-positive, collagen type-I-expressing anulocytes at day 56. This neonatal cellular program results in complete functional restoration of the anulus fibrosus and is completely absent in the adult anulus fibrosus after injury. Knowledge of this regenerative mechanism will allow scientists to further understand and develop treatment algorithms for anulus fibrosus regeneration in the adult with the goal of reducing disc reherniation and subsequent repeat discectomies. The degeneration of the intervertebral disc is associated with the loss of internal pressure of the nucleus pulposus and anulus fibrosus. Bonnevie et al. presented compelling evidence that aberrant mechanosensing of anulus fibrosus cells promotes disc disease progression2. In a series of experiments, the authors demonstrated that the residual strain of the nucleus pulposus generates pre-strain in the outer anulus fibrosus and that the loss of residual strain, as seen in disc herniation, results in short-term apoptosis and the emergence of a fibrotic cell phenotype in the anulus fibrosus. Inhibiting the cellular mechanosensation apparatus abrogates this fibrotic response and resulting degeneration. Therefore, blocking cell contractility pathways may offer a viable target to avoid fibrosis as a result of injury and could be used in conjunction with surgical procedures aimed at restoring proper boundary constraints, such as nucleus pulposus replacement. Sloan et al. utilized a combined tissue-engineering strategy to prevent intervertebral disc degeneration after herniation and subsequent discectomy3. In line with the findings described in the study by Bonnevie et al., Sloan et al. combined a strategy of nucleus pulposus augmentation followed by the repair of the anulus fibrosus using a photo-cross-linked collagen patch. This approach resulted in restored and maintained nucleus pulposus hydration and the healing of the anulus fibrosus defect and eventually culminated in the functional restoration of the torsional and compressive stiffness of the intervertebral disc up to 6 weeks after an injury in an ovine model. Somitogenesis is the process in vertebrate development in which vertebrae, dorsal dermis, and skeletal muscles form from developmental structures of paraxial mesoderm called somites. This highly temporally and spatially regulated process is believed to be controlled by an oscillating genetic clock. Human models to recapitulate and discover species-specific features of human mesoderm development have been previously lacking. Matsuda et al. developed an in vitro modeling system to recapitulate the human segmentation clock4. The group used stepwise differentiation of induced pluripotent stem (iPS) cells into paraxial mesoderm and its derivatives to model human somitogenesis. This eloquent in vitro model allowed the investigators to use the key segmentation clock gene, HES7, to drive luciferase expression to track dynamic oscillations of clock genes in paraxial mesoderm cells, and, by doing so, they identified that the human segmentation clock has a period of about 5 hours, or, every 5 hours, a new somite is formed. Importantly, this model allowed the investigators to assess the function of mutations involved in a human disease associated with segmentation clock defects, such as congenital spondylocostal dysostosis, by using a combination of patient-derived iPS cells and patient-like genetically engineered iPS cells with disease-causing mutations. A human model system of segmentation that can be easily manipulated provides the framework for important discoveries of the human species-specific timing of gene oscillations and the molecular machinery underlying this process in both normal development and disease. Cartilage Regeneration and Osteoarthritis Cartilage has long been described as a tissue without regenerative capacity, and, thus, artificial replacement of large cartilage defects and osteoarthritic joints has been the treatment of choice. With the advent of more sophisticated biochemical and biomolecular tools, it is now possible to challenge these decades-old dogmas. Hsueh et al. analyzed molecular clocks in the form of nonenzymatically deaminated proteins to uncover a position-dependent gradient of protein turnover, which indicated tissue anabolism seen with innate tissue repair capacity5. Using mass spectrometry, the investigators identified the highest protein turnover rates in ankle joints, immediately under the cartilage surface and increased in osteoarthritic cartilage. A gradient was observed, with the highest turnover in the ankle, followed by the knee, and with the lowest turnover in the hip. At the same time, blastema microRNA (miRNA) (miR-21, miR-31, and miR181c), known to be evolutionarily conserved and essential for limb regeneration, was associated with the protein turnover gradient. These observations suggest a dynamic anabolic effect in human limbs, which may reflect an innate regenerative capacity of human cartilage. Inflammatory responses during regeneration are highly dependent on the context, including both timing and cell type. Mild inflammation after injury can support and augment healing. However, excessive or prolonged inflammation at the injury site is deleterious to proper healing. Posttraumatic arthritis, a form of degenerative osteoarthritis, most commonly occurs after a fracture of the articular surface of the joint, which causes acute inflammation. Evidence has suggested that, after an articular fracture, there is substantial synovitis of the joint capsule that causes further immune-induced damage to the joint, creating the myriad of symptoms such as pain and degeneration associated with posttraumatic arthritis. Immune cells thought to be involved in this process are the synovial macrophages. There are 2 types of macrophages: M1, pro-inflammatory, and M2, anti-inflammatory. Each type has distinct temporospatial functions and effects on the process of fracture-healing. Bailey et al. demonstrated that transient synovial macrophage depletion induced intensive synovitis rather than the expected decrease in synovitis 7 days after the fracture6. This study suggested that synovial macrophages play an immunomodulatory role during the repair of articular fractures. Further understanding of the local macrophage subpopulations in the posttraumatic joint will allow for future therapeutic manipulation in an attempt to dampen excessive inflammation, which serves as one of the major components of posttraumatic arthritis. There is little doubt that genetics contributes to the etiology of osteoarthritis. Rai et al. performed an extensive screening of 12 recombinant inbred mouse strains and identified an inverse correlation between the ability to regenerate and to degenerate cartilage7. Regeneration was analyzed using an ear-wound-healing model and an articular full-thickness cartilage regeneration model. Posttraumatic osteoarthritis was induced using a model of destabilization of the medial meniscus. This study design allows for the measurement of genetic correlations of regeneration phenotypes with degeneration phenotypes and showed that osteoarthritis is positively correlated with synovitis and is inversely correlated with the ability to repair cartilage. These findings can now be utilized to identify genes and gene sets that are responsible for mammalian epimorphic regeneration, which will eventually allow for successful in vivo cartilage regeneration. Transforming growth factor beta (TGF-β) signaling has previously been described to play a major role in the development and homeostasis of synovial joints; therefore, TGF-β signaling has been a valuable pathway to study with regard to osteoarthritis. However, TGF-β also has a large number of roles in other organs, making it a difficult direct therapeutic target for osteoarthritis because of the high likelihood of multiorgan side effects. To combat this therapeutic roadblock, Li et al. identified downstream regulators, the interleukin-36 (IL-36) family, of TGF-β in joint development and homeostasis as possible disease-modifying drug targets8. They found that mice lacking Tgfbr2 in Prx1 osteochondral progenitors during development showed joint developmental defects and concurrently found that messenger RNA (mRNA) expression of IL-36α in these mice was significantly upregulated compared with the control group. This developmental role of Tgfbr2 led them to explore its possible role during joint homeostasis. They found that both postnatal ablation of Tgfbr2 in osteochondral progenitors and pharmacological inhibition (by SB-505124) of TGF-β receptor 2 (TGFBR2) led to an osteoarthritis phenotype with an accompanied upregulation of IL-36α and downregulation of IL-36Ra, a receptor antagonist. In a posttraumatic arthritis model, Tgfbr2 expression decreased, and IL-36α increased. They correlated this with human osteoarthritis samples in which they observed a decrease in TGFBR2 and an increase in IL-36α that directly corresponded to the pathological grade of cartilage degeneration. After providing a link between osteoarthritis, TGFBR2, and IL-36α in multiple models of osteoarthritis in mice and humans, Li et al. explored IL-36α as a possible therapeutic target8. They found that an IL-36Ra intra-articular injection attenuates osteoarthritis progression in both the genetic Tgfbr2 deletion and the posttraumatic arthritis model. In primary human chondrocytes from arthritic joints, IL-36N (the human form of IL-36Ra) treatment resulted in reduced expression of matrix metalloprotease, a known major catabolic factor during osteoarthritis. This study therefore introduces the IL-36 family as novel valuable targets to combat osteoarthritis. Bone Regeneration Although the understanding of cellular contributions and molecular signaling pathways during fracture repair has grown, it is still unclear how certain cellular events are initiated and regulated. In a series of elegant surgical manipulations including bone-grafting, van Gastel et al. recently demonstrated that the initial fate decision of periosteal skeletal stem and progenitor cells is dependent on the availability of extracellular lipids9. Immediately after a fracture, local small blood vessels are injured, resulting in a hypoperfusion of the periosteum with subsequent low levels of lipids. In contrast to progenitor cells and osteoblasts, chondrocytes do not rely on fatty acid oxidation; thus, skeletal stem and progenitor cells differentiate into chondrocytes in areas of low lipid levels through activation of Sox9. This fate decision serves as a survival signal for the progenitor cells, as the other choice would be guaranteed apoptosis for the fatty acid oxidation-reliant progenitor cells. In response to injury, skeletal stem and progenitor cells migrate from the periosteum and endosteum to the site of injury to participate in the program of skeletal repair. Matsushita et al. now identified another cell type that is essential for successful long-bone regeneration, the quiescent CXCL12-expressing perisinusoidal bone marrow stromal cell10. These cells convert into a skeletal stem cell-like state after injury and upregulate genes characteristic of the osteoblast lineage, mediated through canonical Wnt signaling. Although these CXCL12-positive cells exhibit little colony-forming ability, they are highly malleable and long-living and thus represent an ideal cellular source for bone tissue regeneration. Osteoclasts are multinucleated cells able to resorb bone extracellular matrix and are essential in the process of bone remodeling and repair. Yahara et al. used an elegant lineage tracing experiment to identify an erythromyeloid progenitor-derived osteoclast precursor in mice11. Yolk-sac macrophages of erythromyeloid progenitor origin generated a long-lasting osteoclast precursor that participates in lifelong bone remodeling during homeostasis and fracture repair. Single-cell RNA sequencing provided compelling evidence that the erythromyeloid progenitor-derived osteoclast precursor develops independently of the hematopoietic stem cell lineage. Perivascular stem cells have been reported to express high levels of osteoinductive proteins and to cause bone healing, primarily through their paracrine influence on resident cells at the injury site. However, it was previously unknown exactly how these cells exert their paracrine effect on bone healing. Xu et al. found that human perivascular stem cells promote proliferation, migration, and osteogenic differentiation of osteoprogenitor cells as well as promote bone repair at the injury site through paracrine signaling via perivascular stem cell-derived extracellular vesicles12. They found that the effects of perivascular stem cells and extracellular vesicles require extracellular vesicle surface tetraspanin activity as well as expression of the binding partners IGSF8 (immunoglobulin superfamily member 8) and PTGFRN (prostaglandin F2 receptor inhibitor) on the recipient osteoprogenitor cells. The inductive effects of perivascular stem cells and extracellular vesicles are concentration-dependent. Low doses of perivascular stem cells and extracellular vesicles demonstrate the greatest osteoprogenitor cell migratory stimulus in vitro, and high doses of perivascular stem cells and extracellular vesicles demonstrate the greatest proliferation and osteogenic stimulus in vitro. This suggests a gradient of extracellular vesicles at the injury site that allows an additional layer of control for differential migratory compared with proliferation and differentiation cues depending on the cell location relative to the injury. Extracellular vesicles are a highly attractive clinical therapeutic target because of their ability to be stored for the long term without compromising their activity, their low immunogenicity and toxicity, and their high permeability; therefore, further research with regard to extracellular vesicles in bone regeneration is a promising line of investigation. Aging is associated not only with a loss in bone mineral density, but also with impaired bone healing after fracture. Research efforts have been undertaken to elucidate the mechanism of impaired fracture-healing in the elderly. Clark et al. further scrutinized the role of macrophages as an important cellular regulator of inflammation during bone healing in the aging animal13. Using RNA sequencing, they demonstrated an increased pro-inflammatory macrophage phenotype in the callus from older animals. The biochemical inhibition of macrophage recruitment to the fracture site resulted in improved bone healing in the older animals, and transcriptional analysis of the remaining local macrophages within the callus revealed similarities to young macrophages, suggesting a detrimental effect of the infiltrating macrophages on bone healing in the elderly. Tendon Healing Adult tendon repair results in scar-mediated healing because adult tendons are unable to regenerate. TGF-β is known to induce fibrotic scar formation in a plethora of tissues, including adult tendons. Kaji et al. identified TGF-β as a major molecular pathway that drives neonatal tendon regeneration14. Through a combination of targeted gene deletion, small molecule inhibition, and lineage tracing, the authors identified TGF-β-dependent and TGF-β-independent mechanisms involved in tendon regeneration. Although the proliferation of Scleraxis-lineage tenocytes and the activation of alpha smooth muscle actin (αSMA)-positive cells do not depend on TGF-β signaling, the proliferation of non-Scleraxis-lineage cells, the recruitment of tenogenic cells, and the eventual functional restoration depend on TGF-β signaling. Further research is needed to identify the underlying reason for the opposite effect of TGF-β signaling during neonatal and adult tendon repair. Extracellular vesicles are known to mediate the inflammatory response after the injury of multiple tissues. Shen et al. found that extracellular vesicles from adipose-derived stem cells, primed with interferon gamma (IFNγ), a pro-inflammatory signal, can reduce early inflammatory cascades in macrophages during a tendon injury, which leads to an improved healing response, including a reduced gap-rupture rate and increasing collagen production at the injury site15. Primed adipose-derived stem cells and extracellular vesicles reduced the production of pro-inflammatory cytokines such as Il1b, decreased the downstream target such as nuclear factor (NF)‐κB, and increased the expression of tendon matrix genes. This study provides a therapeutic opportunity to use primed adipose-derived stem cells and extracellular vesicles as a mechanism to reduce the acute inflammatory response during tendon repair to improve healing rates and increase long-term tendon strength. Upcoming Meetings and Events Related to Orthopaedic Basic Science The 2021 Annual Meeting of the Orthopaedic Research Society (ORS) will be held from February 13 to 16, 2021, in Long Beach, California. The European Calcified Tissue Society will meet from May 8 to 11, 2021, in Brussels, Belgium. The Annual Meeting of the International Society for Stem Cell Research will be held from June 23 to 25, 2021, in Hamburg, Germany. The Gordon Research Conference on Biomaterials and Tissue Engineering will be held from July 18 to 23, 2021, at the Holderness School in Holderness, New Hampshire. The European Orthopaedic Research Society (EORS) Annual Meeting will be held from September 15 to 17, 2021, in Rome, Italy. The American Society for Bone and Mineral Research (ASBMR) 2021 Annual Meeting will be held from October 1 to 4, 2021, in Toronto, Ontario, Canada.

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