What’s New in Musculoskeletal Basic Science 2021

Every month, JBJS publishes a review of the most pertinent and impactful studies from the orthopaedic literature during the previous year in 14 subspecialty areas. This month, co-author Philipp Leucht, MD selected the 5 most clinically compelling findings from among the studies highlighted in the most recent “What’s New in Musculoskeletal Basic Science.” 

Fracture Healing 

–A recent study assessed the importance of periosteal stem and progenitor cells as the key for successful bone healing¹. Using a transgenic mouse line, the investigators demonstrated that the cartilage-to-bone transformation by periosteal cells during bone regeneration is regulated by fibroblast growth factor receptor 3 (FGFR3) signaling. They also showed that periosteal cells transplanted into a nonunion site can overcome the microenvironment that led to failure of union, suggesting their potential in cell-based therapy for the treatment of delayed union or nonunion. 

–Using a murine model of endochondral fracture repair, researchers sought to characterize the kinetics of a novel collagen X biomarker relative to other biological measurements of fracture healing². They demonstrated that the collagen X degradation fragments (collagen X marker [CXM]) can be measured in serum and correlated with the progression of endochondral fracture healing. These findings and those of other recent work underscore the future possibilities of precision medicine in orthopaedics.  

Cartilage and Osteoarthritis 

– A landmark study found that the skeletal stem cells that are recruited to the site of microfracture can be triggered to regenerate articular cartilage by delivering bone morphogenetic protein-2 (BMP-2) and a soluble vascular endothelial growth factor receptor 1 (VEGFR1)³. As noted by JBJS Guest Editorial co-authors Philipp Leucht, MD and Thomas A. Einhorn, MD, “This study showed, for the first time, that biochemical manipulation of the local stem cell niche environment can activate a regenerative response of resident skeletal stem cells that results in a durable articular cartilage regenerate.” 

Heterotopic Ossification 

– Recent investigations have provided new insights into heterotopic bone formation during wound healing. One team of researchers identified the role of nerve growth factor-tropomyosin receptor kinase A (NGF-TrkA) signaling as an important regulator of neural ingrowth and subsequent formation of heterotopic ossification following soft-tissue trauma⁴. 

Single-Cell Transcriptomics 

– The findings of other recent work, say Dr. Leucht and Dr. Einhorn, highlight the need for a combination of scRNA [single-cell RNA] sequencing and techniques such as lineage tracing and genetic manipulation “to fully understand the function of heterogenous cell types within bone both during homeostasis and during regeneration.” One such enlightening study used these methods to define the role of Cxcl12-creER+ labeled reticular cells during regeneration⁵. 

To access the full text of the newest JBJS Guest Editorial, “What’s New in Musculoskeletal Basic Science,” click here.  

A collection of previous OrthoBuzz Guest Editorial summaries can be found here. 

References 

1. Julien A, Perrin S, Duchamp de Lageneste O, Carvalho C, Bensidhoum M, Legeai-Mallet L, Colnot C. FGFR3 in periosteal cells drives cartilage-to-bone transformation in bone repair. Stem Cell Reports. 2020 Oct 13;15(4):955-67.  
2. Working ZM, Morris ER, Chang JC, Coghlan RF, Johnstone B, Miclau T 3rd, Horton WA, Bahney CS. A quantitative serum biomarker of circulating collagen X effectively correlates with endochondral fracture healing. J Orthop Res. 2021 Jan;39(1):53-62. 
3. Murphy MP, Koepke LS, Lopez MT, Tong X, Ambrosi TH, Gulati GS, Marecic O, Wang Y, Ransom RC, Hoover MY, Steininger H, Zhao L, Walkiewicz MP, Quarto N, Levi B, Wan DC, Weissman IL, Goodman SB, Yang F, Longaker MT, Chan CKF. Articular cartilage regeneration by activated skeletal stem cells. Nat Med. 2020 Oct;26(10):1583-92. 
4. Lee S, Hwang C, Marini S, Tower RJ, Qin Q, Negri S, Pagani CA, Sun Y, Stepien DM, Sorkin M, Kubiak CA, Visser ND, Meyers CA, Wang Y, Rasheed HA, Xu J, Miller S, Huber AK, Minichiello L, Cederna PS, Kemp SWP, Clemens TL, James AW, Levi B. NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma. Nat Commun. 2021 Aug 16;12(1):4939. 
5. Matsushita Y, Nagata M, Kozloff KM, Welch JD, Mizuhashi K, Tokavanich N, Hallett SA, Link DC, Nagasawa T, Ono W, Ono N. A Wnt-mediated transformation of the bone marrow stromal cell identity orchestrates skeletal regeneration. Nat Commun. 2020 Jan 16;11(1):332.