Vitamin D and the immunomodulation of rotator cuff injury

Kaitlin A Dougherty, Matthew F Dilisio, Devendra K Agrawal, Kaitlin A Dougherty, Matthew F Dilisio, Devendra K Agrawal

Abstract

Tendon-to-bone healing after rotator cuff repair surgery has a failure rate of 20%-94%. There has been a recent interest to determine the factors that act as determinants between successful and unsuccessful rotator cuff repair. Vitamin D level in patients is one of the factors that have been linked to bone and muscle proliferation and healing, and it may have an effect on tendon-to-bone healing. The purpose of this article is to critically review relevant published research that relates to the effect of vitamin D on rotator cuff tears and subsequent healing. A review of the literature was conducted to identify all studies that investigate the relationship between vitamin D and tendon healing, in addition to its mechanism of action. The data were then analyzed in order to summarize what is currently known about vitamin D, rotator cuff pathology, and tendon-to-bone healing. The activated metabolite of vitamin D, 1α,25-dihydroxyvitamin D3, affects osteoblast proliferation and differentiation. Likewise, vitamin D plays a significant role in the tendon-to-bone healing process by increasing the bone mineral density and strengthening the skeletal muscles. The 1α,25-dihydroxyvitamin D3 binds to vitamin D receptors on myocytes to stimulate growth and proliferation. The form of vitamin D produced by the liver, calcifediol, is a key initiator of the myocyte healing process by moving phosphate into myocytes, which improves function and metabolism. Investigation into the effect of vitamin D on tendons has been sparse, but limited studies have been promising. Matrix metalloproteinases play an active role in remodeling the extracellular matrix (ECM) of tendons, particularly deleterious remodeling of the collagen fibers. Also, the levels of transforming growth factor-β3 positively influence the success of the surgery for rotator cuff repair. In the tendon-to-bone healing process, vitamin D has been shown to successfully influence bone and muscle healing, but more research is needed to delve into the mechanisms of vitamin D as a factor in skeletal tendon health and healing.

Keywords: 1,25-dihydroxyvitamin D; bone; calcium; matrix metalloproteinases; muscle; rotator cuff tear; tendon.

Figures

Figure 1
Figure 1
Potential pathway demonstrating the effects of vitamin D on the RANK receptor and osteocyte differentiation. Abbreviations: NF-κB, nuclear factor-κB; RANK, receptor activator of nuclear factor-κB; RANKL, receptor activator of nuclear factor-κB ligand; VDR, vitamin D receptor; c-Fms, colony-stimulating factor-1 receptor; TRAF6, TNF receptor associated factor-6.
Figure 2
Figure 2
Potential effects of vitamin D on muscle cell differentiation and proliferation. Abbreviation: BMP, bone morphogenetic protein.
Figure 3
Figure 3
Potential effects of vitamin D on tendon inflammation and healing. Note: It has been shown that vitamin D decreases the production of MMPs, thus decreasing inflammation. Abbreviations: JNK, c-Jun N-terminal kinase; MMP, matrix metalloproteinases; NF-κB, nuclear factor-κB; TNF-α, tumor necrosis factor-α; IκBα, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor; AP-1, activator protein 1.

References

    1. Russell RD, Knight JR, Mulligan E, Khazzam MS. Structural integrity after rotator cuff repair does not correlate with patient function and pain: a meta-analysis. J Bone Joint Surg Am. 2014;96:265–271.
    1. Galatz LM, Ball CM, Teefey SA, Middleton WD, Yamaguchi K. The outcome and repair integrity of completely arthroscopically repaired large and massive rotator cuff tears. J Bone Joint Surg Am. 2004;86-A:2019–2024.
    1. Angeline ME, Ma R, Pascual-Garrido C, et al. Effect of diet-induced vitamin D deficiency on rotator cuff healing in a rat model. Am J Sports Med. 2013;42(1):27–34.
    1. Timms PM, Mannan N, Hittman GA, et al. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? QJM. 2002;95(12):787–796.
    1. Robertson CM, Chen CT, Shindle MK, Cordasco FA, Rodeo SA, Warren RF. Failed healing of rotator cuff repair correlates with altered collagenase and gelatinase in supraspinatus and subscapularis tendons. Am J Sports Med. 2012;40(9):1993–2001.
    1. Nossov S, Dines JS, Murrell GA, Rodeo SA, Bedi A. Biologic augmentation of tendon-to-bone healing: scaffolds, mechanical load, vitamin D, and diabetes. Instr Course Lectr. 2014;63:451–462.
    1. Pramyothin P, Holick MF. Vitamin D supplementation. Curr Opin Gastroenterol. 2012;28(2):139–150.
    1. Oh JH, Kim SH, Kim JH, Shin YH, Yoon JP, Oh CH. The level of vitamin D in the serum correlates with fatty degeneration of the muscles of the rotator cuff. J Bone Joint Surg Br. 2009;91(12):1587–1593.
    1. Van Driel M, Koedam M, Buurman CJ, et al. Evidence that both 1α,25-dihydroxyvitamin D3 and 24-dihydroxylated D3 enhance human osteoblast differentiation and mineralization. J Cell Biochem. 2006;99(3):922–935.
    1. Salinger E, Moore J. Perioperative indicators of hypocalcemia in total thyroidectomy: the role of vitamin D and parathyroid hormone. Am J Surg. 2013;206(6):876–881.
    1. Lioben L, Carmeliet G. The delicate balance between vitamin D, calcium and bone homeostasis: lessons learned from intestinal- and osteocyte-specific VDR null mice. J Steroid Biochem Mol Biol. 2013;136:102–106.
    1. Hoenderop J, Dardenne O, van Abel M, et al. Modulation of renal Ca2+ transport protein genes by dietary Ca2+ and 1,25-dihydroxyvitamin D3 in 25-dihydroxyvitamin D3-1α-hydroxylase knockout mice. FASEB J. 2002;16(11):1398–1406.
    1. Burkhart SS, Lo IK. Arthroscopic rotator cuff repair. J Am Acad Orthop Surg. 2006;14(6):333–346.
    1. Yamaguchi K, Tetro AM, Blam O, Evanoff BA, Teefey SA, Middleton WD. Natural history of asymptomatic rotator cuff tears: a longitudinal analysis of asymptomatic tears detected sonographically. J Shoulder Elbow Surg. 2001;10(3):199–203.
    1. Oh LS, Wolf BR, Hall MP, Levy BA, Marx RG. Indications for rotator cuff repair: a systematic review. Clin Orthop Relat Res. 2007;455:52–63.
    1. National Ambulatory Medical Care Survey (NAMCS) 2010. [Accessed March 16, 2015]. Available from: .
    1. Mather RC, 3rd, Koenig L, Acevedo D, et al. The societal and economic value of rotator cuff repair. J Bone Joint Surg Am. 2013;2095(22):1993–2000.
    1. Bahar-Shany K, Ravid A, Koren R. Upregulation of MMP-9 production by TNFα in keratinocytes and its attenuation by vitamin D. J Cell Physiol. 2009;222(3):729–737.
    1. Laird E, McNulty H, Ward M, et al. Vitamin D deficiency is associated with inflammation in older Irish adults. J Clin Endocrinol Metab. 2014;99(5):1807–1815.
    1. Agrawal T, Gupta GK, Agrawal DK. Vitamin D supplementation reduces airway hyperresponsiveness and allergic airway inflammation in a murine model. Clin Exp Allergy. 2013;43(6):672–683.
    1. Nagpal S, Lu J, Boehm MF. Vitamin D analogs: mechanism of action and therapeutic applications. 2001. Curr Med Chem. 2001;8(13):1661–1679.
    1. Gorter EA, Hamdy NAT, Appelman-Dijkstra NM, Schipper IB. The role of vitamin D in human fracture healing: a systematic review of the literature. Bone. 2014;64:288–297.
    1. Chung SW, Oh JH, Gong HS, Kim JY, Kim SH. Factors affecting rotator cuff healing after arthroscopic repair: osteoporosis as one of the independent risk factors. Am J Sports Med. 2011;39(10):2099–2107.
    1. NIH Osteoporosis and Related Bone Diseases National Resource Center Bone mass measurement: What the numbers mean. [Accessed November 28, 2014]. Available from: .
    1. Oh JH, Song BW, Kim SH, et al. Measurement of bone mineral density of bilateral proximal humeri using DXA in patients with unilateral rotator cuff tear. Osteoporos Int. 2014;25(11):2639–2648.
    1. Aoyama E, Kubota S, Khattab HM, Nishida T, Takigawa M. CCH2 enhances RANKL-inducing osteoclast differentiation via direct binding to RANK and OPG. Bone. 2014;73:242–248.
    1. Lézot F, Chesneau J, Navet B, et al. Skeletal consequences of RANKL-blocking antibody (IK22-5) injections during growth: mouse strain disparities and synergic effect with zoledronic acid. Bone. 2014;73:51–59.
    1. Kim T, Lee B, Kwon E, et al. 1,25-dihydroxyvitamin D3 inhibits directly human osteoblastogenesis by down-regulation of the c-Fms and RANK expression. Joint Bone Spine. 2013;80(3):307–314.
    1. Yoskovitz G, Garcia-Giralt N, Rodriguez-Sanz M, et al. Analysis of RANK and RANKL in the post-GWAS context: functional evidence of vitamin D stimulation through a RANKL distal region. J Bone Miner Res. 2013;28(12):2550–2560.
    1. Yousef H, Morgenthaler A, Schlesinger C, Bugaj L, Conboy IM, Schaffer DV. Age-associated increase in BMP signaling inhibits hippocampal neurogenesis. Stem Cells. 2014;33(5):1577–1588.
    1. Avenell A, Gillespie WJ, Gillespie LD, O-Connell D. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev. 2009;15(2):CD000227.
    1. Hedström M, Sjöberg K, Brosjö E, Åström K, Sjöberg H, Dalén N. Positive effects of anabolic steroids, vitamin D and calcium on muscle mass, bone mineral density and clinical function after a hip fracture: a randomized study of 63 women. J Bone Joint Surg. 2002;84(4):497–503.
    1. Cipriani C, Pepe J, Piemonte S, Colangelo L, Cilli M, Minisola S. Vitamin D and its relationship with obesity and muscle. Int J Endocrinol. 2014;2014:841248.
    1. Bartoszewska M, Kamboj M, Patel DP. Vitamin D, muscle function, and exercise performance. Pediatr Clin North Am. 2010;57(3):849–861.
    1. Hamilton B. Vitamin D and human skeletal muscle. Scand J Med Sci Sports. 2010;20(2):182–190.
    1. Sato Y, Iwamoto J, Kanoko T, Satoh K. Low-dose vitamin D prevents muscular atrophy and reduces falls and hip fractures in women after stroke: a randomized controlled trial. Cerebrovasc Dis. 2005;20(3):187–192.
    1. Domingues-Faria C, Chanet A, Salles J, et al. Vitamin D deficiency down-regulates Notch pathway contributing to skeletal muscle atrophy in old wistar rats. Nutr Metab (Lond) 2014;10(11(1)):47.
    1. Schaer M, Schober M, Berger S, Boileau P, Zumstein MA. Biologically based strategies to augment rotator cuff tears. Int J Shoulder Surg. 2012;6(2):51–60.
    1. Bedi A, Kovacevic D, Hettrich C, et al. The effect of matrix metalloproteinase inhibition on tendon-to-bone healing in a rotator cuff repair model. J Shoulder Elbow Surg. 2010;19:384–391.
    1. Reider B. Big D. Am J Sports Med. 2014;42(1):25–26.
    1. Bedi A, Fox AJS, Kovacevic D, Deng X, Warren RF, Rodeo SA. Doxycycline-mediated inhibition of matrix metalloproteinases improves healing after rotator cuff repair. Am J Sports Med. 2010;38:308.
    1. Mall NA, Tanaka MJ, Choi LS, Paletta GA. Factors affecting rotator cuff healing. J Bone Joint Surg. 2014;96(9):778–788.

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