Vos T, Lim SS, Abbafati C, et al. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. The Lancet. 2020;396:1204–22.

Article  Google Scholar 

Peniche Silva C, Müller S, Quirk N, De la Vega R, Coenen M, Evans C, Balmayor E, van Griensven M. Enthesis: Not the same in each localisation – A molecular, histological and biomechanical study. eCM. 2022;44:43–55.

Article  CAS  PubMed  Google Scholar 

• Brown ME, Puetzer JL. Driving native-like zonal enthesis formation in engineered ligaments using mechanical boundary conditions and β-tricalcium phosphate. Acta Biomater. 2022;140:700–16. By exploiting the mechanical boundary conditions of manufacturing collagen gels for ligament mimetics, Brown and Puetzer were able to engineer organized and cellularized entheses at biomimetic scale in vitro.

Article  CAS  PubMed  Google Scholar 

Puetzer JL, Ma T, Sallent I, Gelmi A, Stevens MM. Driving hierarchical collagen fiber formation for functional tendon, ligament, and meniscus replacement. Biomaterials. 2021;269: 120527.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ganji E, Leek C, Duncan W, Patra D, Ornitz DM, Killian ML. Targeted deletion of Fgf9 in tendon disrupts mineralization of the developing enthesis. FASEB J. 2023;37: e22777.

Article  CAS  PubMed  Google Scholar 

Schwartz AG, Lipner JH, Pasteris JD, Genin GM, Thomopoulos S. Muscle loading is necessary for the formation of a functional tendon enthesis. Bone. 2013;55:44–51.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Schwartz AG, Galatz LM, Thomopoulos S. Enthesis regeneration: A role for Gli1+ progenitor cells. Development Dev. 2017;144(7):1159–64.

Vervaecke AJ, Carbone AD, Abraham A, Bernstein Z, Laudier D, Verborgt O, Galatz LM, Huang AH. Tendon progenitor cells as biological augmentation improve functional gait and reduce scar formation after rotator cuff repair. J Shoulder Elbow Surg. 2022;31:2366–80.

Article  PubMed  PubMed Central  Google Scholar 

Vinestock RC, Felsenthal N, Assaraf E, et al. Neonatal enthesis healing involves noninflammatory acellular scar formation through extracellular matrix secretion by resident cells. Am J Pathol. 2022;192:1122–35.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Grinstein M, Dingwall HL, O’Connor LD, Zou K, Capellini TD, Galloway JL. A distinct transition from cell growth to physiological homeostasis in the tendon. eLife. 2019;8:e48689.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Walia B, Li TM, Crosio G, Montero AM, Huang AH. Axin2-lineage cells contribute to neonatal tendon regeneration. Connect Tissue Res. 2022;63:530–43.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Walia B, Huang AH. Tendon stem progenitor cells: Understanding the biology to inform therapeutic strategies for tendon repair. J Orthop Res. 2019;37:1270–80.

Article  PubMed  Google Scholar 

Killian ML, Thomopoulos S. Scleraxis is required for the development of a functional tendon enthesis. FASEB j. 2016;30:301–11.

Article  CAS  PubMed  Google Scholar 

Liu H, Xu J, Lan Y, Lim H-W, Jiang R. The Scleraxis transcription factor directly regulates multiple distinct molecular and cellular processes during early tendon cell differentiation. Front Cell Dev Biol. 2021;9: 654397.

Article  PubMed  PubMed Central  Google Scholar 

Blitz E, Sharir A, Akiyama H, Zelzer E. Tendon-bone attachment unit is formed modularly by a distinct pool of Scx - and Sox9 -positive progenitors. Development. 2013;140:2680–90.

Article  CAS  PubMed  Google Scholar 

•• Kult S, Olender T, Osterwalder M, et al. Bi-fated tendon-to-bone attachment cells are regulated by shared enhancers and KLF transcription factors. eLife. 2021;10:e55361. Our understanding of the cell fate at musculoskeletal interfaces was rapidly advanced by Kult et al., whose work describes multi-omic approaches at the single cell level for describing the epigenetic and transcriptomic profile of attachment resident cells. These attachment-resident cells, which are uniquely identified during development as both Sox9+ and Scx+, have unique and overlapping features of cells in adjacent tissues, and these insights can be leveraged for improving interface regeneration using epigenetic modifiers for controlling cell fate.

Best KT, Loiselle AE. Scleraxis lineage cells contribute to organized bridging tissue during tendon healing and identify a subpopulation of resident tendon cells. FASEB j. 2019;33:8578–87.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ackerman JE, Best KT, Muscat SN, Pritchett EM, Nichols AEC, Wu C-L, Loiselle AE. Defining the spatial-molecular map of fibrotic tendon healing and the drivers of Scleraxis-lineage cell fate and function. Cell Rep. 2022;41: 111706.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Best KT, Korcari A, Mora KE, Nichols AE, Muscat SN, Knapp E, Buckley MR, Loiselle AE. Scleraxis-lineage cell depletion improves tendon healing and disrupts adult tendon homeostasis. eLife. 2021;10:e62203.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Korcari A, Nichols AE, Buckley MR, Loiselle AE. Scleraxis-lineage cells are required for tendon homeostasis and their depletion induces an accelerated extracellular matrix aging phenotype. eLife. 2023;12:e84194.

Article  PubMed  PubMed Central  Google Scholar 

Huang AH, Watson SS, Wang L, Baker B, Akiyama H, Brigande JV, et al. Requirement for Scleraxis in the recruitment of mesenchymal progenitors during embryonic tendon elongation. Development Dev. 2019;146(20):dev182782.

Ideo K, Tokunaga T, Shukunami C, Takimoto A, Yoshimoto Y, Yonemitsu R, Karasugi T, Mizuta H, Hiraki Y, Miyamoto T. Role of Scx+/Sox9+ cells as potential progenitor cells for postnatal supraspinatus enthesis formation and healing after injury in mice. PLoS One. 2020;15: e0242286.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Niu X, Subramanian A, Hwang TH, Schilling TF, Galloway JL. Tendon cell regeneration is mediated by attachment site-resident progenitors and BMP signaling. Curr Biol. 2020;30:3277-3292.e5.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Howell K, Chien C, Bell R, Laudier D, Tufa SF, Keene DR, Andarawis-Puri N, Huang AH. Novel model of tendon regeneration reveals distinct cell mechanisms underlying regenerative and fibrotic tendon healing. Sci Rep. 2017;7:45238.

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Moser HL, Abraham AC, Howell K, Laudier D, Zumstein MA, Galatz LM, Huang AH. Cell lineage tracing and functional assessment of supraspinatus tendon healing in an acute repair murine model. J Orthop Res. 2021;39:1789–99.

Article  PubMed  Google Scholar 

Breidenbach AP, Aschbacher-Smith L, Lu Y, et al. Ablating hedgehog signaling in tenocytes during development impairs biomechanics and matrix organization of the adult murine patellar tendon enthesis. J Orthop Res. 2015;33:1142–51.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Dyment NA, Breidenbach AP, Schwartz AG, et al. Gdf5 progenitors give rise to fibrocartilage cells that mineralize via hedgehog signaling to form the zonal enthesis. Dev Biol. 2015;405:96–107.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Fang F, Schwartz AG, Moore ER, Sup ME, Thomopoulos S. Primary cilia as the nexus of biophysical and hedgehog signaling at the tendon enthesis. Sci Adv. 2020;6:eabc1799.

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Schwartz AG, Long F, Thomopoulos S. Enthesis fibrocartilage cells originate from a population of Hedgehog-responsive cells modulated by the loading environment. Development. 2015;142:196–206.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Felsenthal N, Rubin S, Stern T, Krief S, Pal D, Pryce BA, et al. Development of migrating tendon-bone attachments involves replacement of progenitor populations. Development Dev. 2018;145(24):dev165381.

Jing D, Li C, Yao K, Xie X, Wang P, Zhao H, Feng JQ, Zhao Z, Wu Y, Wang J. The vital role of Gli1+ mesenchymal stem cells in tissue development and homeostasis. J Cell Physiol. 2021;236:6077–89.

Article  CAS  PubMed  Google Scholar 

Fang F, Xiao Y, Zelzer E, Leong KW, Thomopoulos S. A unique mineralizing pool of Gli1+ stem cells builds the tendon enthesis and demonstrates therapeutic potential. 2022. https://doi.org/10.1101/2022.02.17.480929.

Eyal S, Kult S, Rubin S, et al. Bone morphology is regulated modularly by global and regional genetic programs. Development Dev. 2019;146(14):dev167882.

Duboc V, Sulaiman F, Feneck E, Kucharska A, Bell D, Holder-Espinasse M, et al. Tbx4 function during hindlimb development reveals a novel mechanism to explain the origins of proximal limb defects. Development Dev. 2021;148(19):dev199580.

Roberts RR, Bobzin L, Teng CS, Pal D, Tuzon CT, Schweitzer R, et al. FGF signaling patterns cell fate at the interface between tendon and bone. Development Dev. 2019;146(15):dev170241.

Vieira WA, Wells KM, Raymond MJ, De Souza L, Garcia E, McCusker CD. FGF, BMP, and RA signaling are sufficient for the induction of complete limb regeneration from non-regenerating wounds on Ambystoma mexicanum limbs. Dev Biol. 2019;451:146–57.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wernlé KK, Sonnenfelt MA, Leek CC, Ganji E, Sullivan AL, Offutt C, et al. Loss of Fgfr1 and Fgfr2 in Scleraxis-lineage cells leads to enlarged bone eminences and attachment cell death. Dev Dyn. 2023;252(9):1180–8.

Kamalitdinov TB, Fujino K, Keith Lang S, Jiang X, Madi R, Evans MK, Zgonis MH, Kuntz AF, Dyment NA. Targeting the hedgehog signaling pathway to improve tendon-to-bone integration. Osteoarthritis Cartilage. 2023;31:1202–13.

Article  PubMed  Google Scholar 

Kopinke D, Norris AM, Mukhopadhyay S. Developmental and regenerative paradigms of cilia regulated hedgehog signaling. Semin Cell Dev Biol. 2021;110:89–103.

Article  CAS  PubMed  Google Scholar 

Xiao H, Zhang T, Li C, et al. Mechanical stimulation promotes enthesis injury repair by mobilizing Prrx1+ cells via ciliary TGF-β signaling. eLife. 2022;11:e73614.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Subramanian A, Schilling TF. Tendon development and musculoskele