What’s New in Musculoskeletal Basic Science 2020

Every month, JBJS publishes a review of the most pertinent and impactful studies published in the orthopaedic literature during the previous year in 13 subspecialties. Click here for a collection of all such OrthoBuzz specialty-update summaries.

This month, co-author Philipp Leucht, MD selected the most compelling findings from the 15 studies summarized in the December 2, 2020 “What’s New in Musculoskeletal Basic Science.”

Spine: Annulus Fibrosus Findings
The relatively high prevalence of repeat discectomies has caused researchers to focus on characteristics of the annulus fibrosus, the healing of which often remains incomplete after disc herniation.

–Knowing that the neonatal annulus fibrosus shows regenerative capacity, researchers recently identified Scleraxis-lineage cells as the main contributors to those regenerative properties.¹ They discovered that the neonatal cellular programming that results in complete functional restoration of the annulus fibrosus is completely absent in the adult annulus fibrosus after injury. Knowledge of this regenerative mechanism could help scientists develop new treatments for annulus fibrosus regeneration in adults.

–Related research demonstrated that the residual strain of the healthy nucleus pulposus generates pre-strain in the outer annulus 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 annulus fibrosus.² Blocking cell contractility pathways may therefore offer a viable target to prevent post-injury fibrosis.

Spine: Somitogenesis
–The somitogenesis process in vertebrate development is believed to be controlled by an oscillating genetic “clock.” Researchers developed an in vitro modeling system to recapitulate the human segmentation clock,³ determining that the clock causes a new somite to be formed every 5 hours. This model allowed investigators to assess the function of mutations involved in segmentation defects such as congenital spondylocostal dysostosis. This easily manipulated model could provide the framework for discoveries of the gene oscillations and molecular underpinnings in both normal and abnormal vertebral development.

Osteoarthritis
–Transforming growth factor beta (TGF-β) signaling has been revealing in studying osteoarthritis. Researchers found that mice lacking  in Prx1 osteochondral progenitors during development showed joint developmental defects.⁴ They further found that both postnatal ablation of Tgfbr2 in osteochondral progenitors and pharmacological inhibition of TGF-β receptor 2 led to an osteoarthritis phenotype with accompanied upregulation of the receptor antagonist IL-36α. They then discovered that an IL-36Ra intra-articular injection attenuates osteoarthritis progression in both Tgfbr2-deletion and posttraumatic arthritis models, confirming the IL-36 family as a viable target in fighting osteoarthritis.

Bone Regeneration
–Skeletal stem and progenitor cells migrate to sites of damage after an injury to participate in the repair process. Researchers recently discovered that the quiescent CXCL12-expressing perisinusoidal bone marrow stromal cells also participate in the repair process⁵ by converting into a skeletal stem-cell-like state after injury. These CCXL12-positive cells are highly malleable and long-living and thus represent an ideal source for bone tissue regeneration.

References

1. Torre OM, Mroz V, Benitez ARM, Huang AH, Iatridis JC. Neonatal annulus fibrosus regeneration occurs via recruitment and proliferation of Scleraxis-lineage cells. NPJ Regen Med.2019 Dec 20;4:23.
2. Bonnevie ED, Gullbrand SE, Ashinsky BG, Tsinman TK, Elliott DM, Chao PG, Smith HE, Mauck RL. Aberrant mechanosensing in injured intervertebral discs as a result of boundary-constraint disruption and residual-strain loss. Nat Biomed Eng.2019 Dec;3(12):998-1008. Epub 2019 Oct 14.
3. Matsuda M, Yamanaka Y, Uemura M, Osawa M, Saito MK, Nagahashi A, Nishio M, Guo L, Ikegawa S, Sakurai S, Kihara S, Maurissen TL, Nakamura M, Matsumoto T, Yoshitomi H, Ikeya M, Kawakami N, Yamamoto T, Woltjen K, Ebisuya M, Toguchida J, Alev C. Recapitulating the human segmentation clock with pluripotent stem cells. 2020 Apr;580(7801):124-9. Epub 2020 Apr 1.
4. Li T, Chubinskaya S, Esposito A, Jin X, Tagliafierro L, Loeser R, Hakimiyan AA, Longobardi L, Ozkan H, Spagnoli A. TGF-β type 2 receptor-mediated modulation of the IL-36 family can be therapeutically targeted in osteoarthritis. Sci Transl Med.2019 May 8;11(491):eaan2585.
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.