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Bone biology

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Sclerostin inhibition alleviates breast cancer–induced bone metastases and muscle weakness
Eric Hesse, … , Hiroaki Saito, Hanna Taipaleenmäki
Eric Hesse, … , Hiroaki Saito, Hanna Taipaleenmäki
Published April 9, 2019
Citation Information: JCI Insight. 2019. https://doi.org/10.1172/jci.insight.125543.
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Sclerostin inhibition alleviates breast cancer–induced bone metastases and muscle weakness

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Abstract

Breast cancer bone metastases often cause a debilitating non-curable condition with osteolytic lesions, muscle weakness and a high mortality. Current treatment comprises chemotherapy, irradiation, surgery and anti-resorptive drugs that restrict but do not revert bone destruction. In metastatic breast cancer cells, we determined the expression of sclerostin, a soluble Wnt inhibitor that represses osteoblast differentiation and bone formation. In mice with breast cancer bone metastases, pharmacological inhibition of sclerostin using an anti-sclerostin antibody (Scl-Ab) reduced metastases without tumor cell dissemination to other distant sites. Sclerostin inhibition prevented the cancer-induced bone destruction by augmenting osteoblast-mediated bone formation and reducing osteoclast-dependent bone resorption. During advanced disease, NF-κB and p38 signaling was increased in muscles in a TGF-β1-dependent manner, causing muscle fiber atrophy, muscle weakness and tissue regeneration with an increase in Pax7-positive satellite cells. Scl-Ab treatment restored NF-κB and p38 signaling, the abundance of Pax7-positive cells and ultimately muscle function. These effects improved the overall health condition and expanded the life span of cancer-bearing mice. Together, these results demonstrate that pharmacological inhibition of sclerostin reduces bone metastatic burden and muscle weakness with a prolongation of the survival time. This might provide novel options for treating musculoskeletal complications in breast cancer patients.

Authors

Eric Hesse, Saskia Schröder, Diana Brandt, Jenny Pamperin, Hiroaki Saito, Hanna Taipaleenmäki

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PTHrP targets HDAC4 and HDAC5 to repress chondrocyte hypertrophy
Shigeki Nishimori, … , Andrew B. Lassar, Henry M. Kronenberg
Shigeki Nishimori, … , Andrew B. Lassar, Henry M. Kronenberg
Published March 7, 2019
Citation Information: JCI Insight. 2019;4(5):e97903. https://doi.org/10.1172/jci.insight.97903.
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PTHrP targets HDAC4 and HDAC5 to repress chondrocyte hypertrophy

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Abstract

During endochondral bone formation, chondrocyte hypertrophy represents a crucial turning point from chondrocyte differentiation to bone formation. Both parathyroid hormone-related protein (PTHrP) and histone deacetylase 4 (HDAC4) inhibit chondrocyte hypertrophy. Using multiple mouse genetics models, we demonstrate in vivo that HDAC4 is required for the effects of PTHrP on chondrocyte differentiation. We further show in vivo that PTHrP leads to reduced HDAC4 phosphorylation at the 14-3-3–binding sites and subsequent HDAC4 nuclear translocation. The Hdac4-KO mouse shares a similar but milder phenotype with the Pthrp-KO mouse, indicating the possible existence of other mediators of PTHrP action. We identify HDAC5 as an additional mediator of PTHrP signaling. While the Hdac5-KO mouse has no growth plate phenotype at birth, the KO of Hdac5 in addition to the KO of Hdac4 is required to block fully PTHrP action on chondrocyte differentiation at birth in vivo. Finally, we show that PTHrP suppresses myocyte enhancer factor 2 (Mef2) action that allows runt-related transcription factor 2 (Runx2) mRNA expression needed for chondrocyte hypertrophy. Our results demonstrate that PTHrP inhibits chondrocyte hypertrophy and subsequent bone formation in vivo by allowing HDAC4 and HDAC5 to block the Mef2/Runx2 signaling cascade. These results explain the phenotypes of several genetic abnormalities in humans.

Authors

Shigeki Nishimori, Forest Lai, Mieno Shiraishi, Tatsuya Kobayashi, Elena Kozhemyakina, Tso-Pang Yao, Andrew B. Lassar, Henry M. Kronenberg

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Intestinal clock system regulates skeletal homeostasis
Masanobu Kawai, … , Keiichi Ozono, Toshimi Michigami
Masanobu Kawai, … , Keiichi Ozono, Toshimi Michigami
Published February 7, 2019
Citation Information: JCI Insight. 2019. https://doi.org/10.1172/jci.insight.121798.
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Intestinal clock system regulates skeletal homeostasis

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Abstract

The circadian clock network is an evolutionally conserved system involved in the regulation of metabolic homeostasis; however, its impacts on skeletal metabolism remain largely unknown. We herein demonstrated that circadian clock network in the intestines plays pivotal roles in skeletal metabolism such that the lack of Bmal1 gene in the intestines (Bmal1Int-/- mice) caused bone loss with bone resorption being activated and bone formation suppressed. Mechanistically, Clock interaction with Vitamin D receptor (Vdr) accelerated its binding to VDR response element by enhancing histone acetylation in a circadian-dependent manner, and this was lost in Bmal1Int-/- mice because nuclear translocation of Clock required the presence of Bmal1. Accordingly, the rhythmic expression of Vdr-target genes involved in transcellular calcium (Ca) absorption was created, and this was not observed in Bmal1Int-/- mice. As a result, transcellular Ca absorption was impaired and bone resorption was activated in Bmal1Int-/- mice. Additionally, sympathetic tone, the activation of which suppresses bone formation, was elevated through afferent vagal nerves in Bmal1Int-/- mice, the blockade of which partially recovered bone loss by increasing bone formation and suppressing bone resorption in Bmal1Int-/- mice. These results demonstrate that the intestinal circadian system regulates skeletal bone homeostasis.

Authors

Masanobu Kawai, Saori Kinoshita, Miwa Yamazaki, Keiko Yamamoto, Clifford J. Rosen, Shigeki Shimba, Keiichi Ozono, Toshimi Michigami

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Hypomorphic mutations of TRIP11 cause odontochondrodysplasia
Anika Wehrle, … , Martin Lowe, Ekkehart Lausch
Anika Wehrle, … , Martin Lowe, Ekkehart Lausch
Published February 7, 2019
Citation Information: JCI Insight. 2019;4(3):e124701. https://doi.org/10.1172/jci.insight.124701.
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Hypomorphic mutations of TRIP11 cause odontochondrodysplasia

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Abstract

Odontochondrodysplasia (ODCD) is an unresolved genetic disorder of skeletal and dental development. Here, we show that ODCD is caused by hypomorphic TRIP11 mutations, and we identify ODCD as the nonlethal counterpart to achondrogenesis 1A (ACG1A), the known null phenotype in humans. TRIP11 encodes Golgi-associated microtubule-binding protein 210 (GMAP-210), an essential tether protein of the Golgi apparatus that physically interacts with intraflagellar transport 20 (IFT20), a component of the ciliary intraflagellar transport complex B. This association and extraskeletal disease manifestations in ODCD point to a cilium-dependent pathogenesis. However, our functional studies in patient-derived primary cells clearly support a Golgi-based disease mechanism. In spite of reduced abundance, residual GMAP variants maintain partial Golgi integrity, normal global protein secretion, and subcellular distribution of IFT20 in ODCD. These functions are lost when GMAP-210 is completely abrogated in ACG1A. However, a similar defect in chondrocyte maturation is observed in both disorders, which produces a cellular achondrogenesis phenotype of different severity, ensuing from aberrant glycan processing and impaired extracellular matrix proteoglycan secretion by the Golgi apparatus.

Authors

Anika Wehrle, Tomasz M. Witkos, Sheila Unger, Judith Schneider, John A. Follit, Johannes Hermann, Tim Welting, Virginia Fano, Marja Hietala, Nithiwat Vatanavicharn, Katharina Schoner, Jürgen Spranger, Miriam Schmidts, Bernhard Zabel, Gregory J. Pazour, Agnes Bloch-Zupan, Gen Nishimura, Andrea Superti-Furga, Martin Lowe, Ekkehart Lausch

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Multimodal imaging guides surgical management in a preclinical spinal implant infection model
Stephen D. Zoller, … , Kevin P. Francis, Nicholas M. Bernthal
Stephen D. Zoller, … , Kevin P. Francis, Nicholas M. Bernthal
Published February 7, 2019
Citation Information: JCI Insight. 2019;4(3):e124813. https://doi.org/10.1172/jci.insight.124813.
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Multimodal imaging guides surgical management in a preclinical spinal implant infection model

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Abstract

Spine implant infections portend disastrous outcomes, as diagnosis is challenging and surgical eradication is at odds with mechanical spinal stability. Current imaging modalities can detect anatomical alterations and anomalies but cannot differentiate between infection and aseptic loosening, diagnose specific pathogens, or delineate the extent of an infection. Herein, a fully human monoclonal antibody 1D9, recognizing the immunodominant staphylococcal antigen A on the surface of Staphylococcus aureus, was assessed as a nuclear and fluorescent imaging probe in a preclinical model of S. aureus spinal implant infection, utilizing bioluminescently labeled bacteria to confirm the specificity and sensitivity of this targeting. Postoperative mice were administered 1D9 probe dual labeled with 89-zirconium (89Zr) and a bars represent SEM dye (NIR680) (89Zr-NIR680-1D9), and PET-CT and in vivo fluorescence and bioluminescence imaging were performed. The 89Zr-NIR680-1D9 probe accurately diagnosed both acute and subacute implant infection and permitted fluorescent image-guided surgery for selective debridement of infected tissue. Therefore, a single probe could noninvasively diagnose an infection and facilitate image-guided surgery to improve the clinical management of implant infections.

Authors

Stephen D. Zoller, Howard Y. Park, Tove Olafsen, Charles Zamilpa, Zachary D.C. Burke, Gideon Blumstein, William L. Sheppard, Christopher D. Hamad, Kellyn R. Hori, Jen-Chieh Tseng, Julie Czupryna, Craig McMannus, Jason T. Lee, Mafalda Bispo, Francisco Romero Pastrana, Elisa J.M. Raineri, Jeffery F. Miller, Lloyd S. Miller, Jan Maarten van Dijl, Kevin P. Francis, Nicholas M. Bernthal

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NF-κB/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification
Emilie Barruet, … , Mary C. Nakamura, Edward C. Hsiao
Emilie Barruet, … , Mary C. Nakamura, Edward C. Hsiao
Published November 15, 2018
Citation Information: JCI Insight. 2018;3(22):e122958. https://doi.org/10.1172/jci.insight.122958.
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NF-κB/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification

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Abstract

BACKGROUND. Inflammation helps regulate normal growth and tissue repair. Although bone morphogenetic proteins (BMPs) and inflammation are known contributors to abnormal bone formation, how these pathways interact in ossification remains unclear. METHODS. We examined this potential link in patients with fibrodysplasia ossificans progressiva (FOP), a genetic condition of progressive heterotopic ossification caused by activating mutations in the Activin A type I receptor (ACVR1/ALK2). FOP patients show exquisite sensitivity to trauma, suggesting that BMP pathway activation may alter immune responses. We studied primary blood, monocyte, and macrophage samples from control and FOP subjects using multiplex cytokine, gene expression, and protein analyses; examined CD14+ primary monocyte and macrophage responses to TLR ligands; and assayed BMP, TGF-β activated kinase 1 (TAK1), and NF-κB pathways. RESULTS. FOP subjects at baseline without clinically evident heterotopic ossification showed increased serum IL-3, IL-7, IL-8, and IL-10. CD14+ primary monocytes treated with the TLR4 activator LPS showed increased CCL5, CCR7, and CXCL10; abnormal cytokine/chemokine secretion; and prolonged activation of the NF-κB pathway. FOP macrophages derived from primary monocytes also showed abnormal cytokine/chemokine secretion, increased TGF-β production, and p38MAPK activation. Surprisingly, SMAD phosphorylation was not significantly changed in the FOP monocytes/macrophages. CONCLUSIONS. Abnormal ACVR1 activity causes a proinflammatory state via increased NF-κB and p38MAPK activity. Similar changes may contribute to other types of heterotopic ossification, such as in scleroderma and dermatomyositis; after trauma; or with recombinant BMP-induced bone fusion. Our findings suggest that chronic antiinflammatory treatment may be useful for heterotopic ossification.

Authors

Emilie Barruet, Blanca M. Morales, Corey J. Cain, Amy N. Ton, Kelly L. Wentworth, Tea V. Chan, Tania A. Moody, Mariëlle C. Haks, Tom H.M. Ottenhoff, Judith Hellman, Mary C. Nakamura, Edward C. Hsiao

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1,25-Dihydroxyvitamin D suppresses M1 macrophages and promotes M2 differentiation at bone injury sites
Samiksha Wasnik, … , Kin-Hing William Lau, Xiaolei Tang
Samiksha Wasnik, … , Kin-Hing William Lau, Xiaolei Tang
Published September 6, 2018
Citation Information: JCI Insight. 2018;3(17):e98773. https://doi.org/10.1172/jci.insight.98773.
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1,25-Dihydroxyvitamin D suppresses M1 macrophages and promotes M2 differentiation at bone injury sites

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Abstract

An indispensable role of macrophages in bone repair has been well recognized. Previous data have demonstrated the copresence of M1 macrophages and mesenchymal stem cells (MSCs) during the proinflammatory stage of bone repair. However, the exact role of M1 macrophages in MSC function and bone repair is unknown. This study aimed to define the role of M1 macrophages at bone injury sites via the function of 1,25-Dihydroxyvitamin D (1,25[OH]2D) in suppressing M1 but promoting M2 differentiation. We showed that 1,25(OH)2D suppressed M1 macrophage–mediated enhancement of MSC migration. Additionally, 1,25(OH)2D inhibited M1 macrophage secretion of osteogenic proteins (i.e., Oncostatin M, TNF-α, and IL-6). Importantly, the 1,25(OH)2D-mediated suppression of osteogenic function in M1 macrophages at the proinflammatory stage was associated with 1,25(OH)2D-mediated reduction of MSC abundance, compromised osteogenic potential of MSCs, and impairment of fracture repair. Furthermore, outside the proinflammatory stage, 1,25(OH)2D treatment did not suppress fracture repair. Accordingly, our data support 2 conclusions: (a) M1 macrophages are important for the recruitment and osteogenic priming of MSCs and, hence, are necessary for fracture repair, and (b) under vitamin D–sufficient conditions, 1,25(OH)2D treatment is unnecessary and can be detrimental if provided during the proinflammatory stage of fracture healing.

Authors

Samiksha Wasnik, Charles H. Rundle, David J. Baylink, Mohammad Safaie Yazdi, Edmundo E. Carreon, Yi Xu, Xuezhong Qin, Kin-Hing William Lau, Xiaolei Tang

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Sclerostin neutralization unleashes the osteoanabolic effects of Dkk1 inhibition
Phillip C. Witcher, … , Gabriela G. Loots, Alexander G. Robling
Phillip C. Witcher, … , Gabriela G. Loots, Alexander G. Robling
Published June 7, 2018
Citation Information: JCI Insight. 2018;3(11):e98673. https://doi.org/10.1172/jci.insight.98673.
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Sclerostin neutralization unleashes the osteoanabolic effects of Dkk1 inhibition

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Abstract

The WNT pathway has become an attractive target for skeletal therapies. High-bone-mass phenotypes in patients with loss-of-function mutations in the LRP5/6 inhibitor Sost (sclerosteosis), or in its downstream enhancer region (van Buchem disease), highlight the utility of targeting Sost/sclerostin to improve bone properties. Sclerostin-neutralizing antibody is highly osteoanabolic in animal models and in human clinical trials, but antibody-based inhibition of another potent LRP5/6 antagonist, Dkk1, is largely inefficacious for building bone in the unperturbed adult skeleton. Here, we show that conditional deletion of Dkk1 from bone also has negligible effects on bone mass. Dkk1 inhibition increases Sost expression, suggesting a potential compensatory mechanism that might explain why Dkk1 suppression lacks anabolic action. To test this concept, we deleted Sost from osteocytes in, or administered sclerostin neutralizing antibody to, mice with a Dkk1-deficient skeleton. A robust anabolic response to Dkk1 deletion was manifest only when Sost/sclerostin was impaired. Whole-body DXA scans, μCT measurements of the femur and spine, histomorphometric measures of femoral bone formation rates, and biomechanical properties of whole bones confirmed the anabolic potential of Dkk1 inhibition in the absence of sclerostin. Further, combined administration of sclerostin and Dkk1 antibody in WT mice produced a synergistic effect on bone gain that greatly exceeded individual or additive effects of the therapies, confirming the therapeutic potential of inhibiting multiple WNT antagonists for skeletal health. In conclusion, the osteoanabolic effects of Dkk1 inhibition can be realized if sclerostin upregulation is prevented. Anabolic therapies for patients with low bone mass might benefit from a strategy that accounts for the compensatory milieu of WNT inhibitors in bone tissue.

Authors

Phillip C. Witcher, Sara E. Miner, Daniel J. Horan, Whitney A. Bullock, Kyung-Eun Lim, Kyung Shin Kang, Alison L. Adaniya, Ryan D. Ross, Gabriela G. Loots, Alexander G. Robling

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Canagliflozin triggers the FGF23/1,25-dihydroxyvitamin D/PTH axis in healthy volunteers in a randomized crossover study
Jenny E. Blau, … , Kristina I. Rother, Simeon I. Taylor
Jenny E. Blau, … , Kristina I. Rother, Simeon I. Taylor
Published April 19, 2018
Citation Information: JCI Insight. 2018;3(8):e99123. https://doi.org/10.1172/jci.insight.99123.
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Canagliflozin triggers the FGF23/1,25-dihydroxyvitamin D/PTH axis in healthy volunteers in a randomized crossover study

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Abstract

BACKGROUND. Sodium glucose cotransporter-2 (SGLT2) inhibitors are the most recently approved class of drugs for type 2 diabetes and provide both glycemic efficacy and cardiovascular risk reduction. A number of safety issues have been identified, including treatment-emergent bone fractures. To understand the overall clinical profile, these safety issues must be balanced against an attractive efficacy profile. Our study was designed to investigate pathophysiological mechanisms mediating treatment-emergent adverse effects on bone health. METHODS. We conducted a single-blind randomized crossover study in hospitalized healthy adults (n = 25) receiving either canagliflozin (300 mg/d) or placebo for 5 days. The primary end-point was the drug-induced change in AUC for plasma intact fibroblast growth factor 23 (FGF23) immunoactivity between 24 and 72 hours. RESULTS. Canagliflozin administration increased placebo-subtracted mean levels of serum phosphorus (+16%), plasma FGF23 (+20%), and plasma parathyroid hormone (PTH) (+25%), while decreasing the level of 1,25-dihydroxyvitamin D (–10%). There was substantial interindividual variation in the magnitude of each of these pharmacodynamic responses. The increase in plasma FGF23 was correlated with the increase in serum phosphorus, and the decrease in plasma 1,25-dihydroxyvitamin D was correlated with the increase in plasma FGF23. CONCLUSIONS. Canagliflozin induced a prompt increase in serum phosphorus, which triggers downstream changes in FGF23, 1,25-dihydroxyvitamin D, and PTH, with potential to exert adverse effects on bone health. These pharmacodynamic data provide a foundation for future research to elucidate pathophysiological mechanisms of adverse effects on bone health, with the objective of devising therapeutic strategies to mitigate the drug-associated fracture risk. TRIAL REGISTRATION. ClinicalTrial.gov (NCT02404870). FUNDING. Supported by the Intramural Program of NIDDK.

Authors

Jenny E. Blau, Viviana Bauman, Ellen M. Conway, Paolo Piaggi, Mary F. Walter, Elizabeth C. Wright, Shanna Bernstein, Amber B. Courville, Michael T. Collins, Kristina I. Rother, Simeon I. Taylor

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The metalloproteinase-proteoglycans ADAMTS7 and ADAMTS12 provide an innate, tendon-specific protective mechanism against heterotopic ossification
Timothy J. Mead, … , David E. Birk, Suneel S. Apte
Timothy J. Mead, … , David E. Birk, Suneel S. Apte
Published April 5, 2018
Citation Information: JCI Insight. 2018;3(7):e92941. https://doi.org/10.1172/jci.insight.92941.
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The metalloproteinase-proteoglycans ADAMTS7 and ADAMTS12 provide an innate, tendon-specific protective mechanism against heterotopic ossification

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Abstract

Heterotopic ossification (HO) is a significant clinical problem with incompletely resolved mechanisms. Here, the secreted metalloproteinases ADAMTS7 and ADAMTS12 are shown to comprise a unique proteoglycan class that protects against a tendency toward HO in mouse hindlimb tendons, menisci, and ligaments. Adamts7 and Adamts12 mRNAs were sparsely expressed in murine forelimbs but strongly coexpressed in hindlimb tendons, skeletal muscle, ligaments, and meniscal fibrocartilage. Adamts7–/– Adamts12–/– mice, but not corresponding single-gene mutants, which demonstrated compensatory upregulation of the intact homolog mRNA, developed progressive HO in these tissues after 4 months of age. Adamts7–/– Adamts12–/– tendons had abnormal collagen fibrils, accompanied by reduced levels of the small leucine-rich proteoglycans (SLRPs) biglycan, fibromodulin, and decorin, which regulate collagen fibrillogenesis. Bgn–/0 Fmod–/– mice are known to have a strikingly similar hindlimb HO to that of Adamts7–/– Adamts12–/– mice, implicating fibromodulin and biglycan reduction as a likely mechanism underlying HO in Adamts7–/– Adamts12–/– mice. Interestingly, degenerated human biceps tendons had reduced ADAMTS7 mRNA compared with healthy biceps tendons, which expressed both ADAMTS7 and ADAMTS12. These results suggest that ADAMTS7 and ADAMTS12 drive an innate pathway protective against hindlimb HO in mice and may be essential for human tendon health.

Authors

Timothy J. Mead, Daniel R. McCulloch, Jason C. Ho, Yaoyao Du, Sheila M. Adams, David E. Birk, Suneel S. Apte

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